System for Tailoring Dialysis Treatment Based on Sensed Potassium Concentration, Patient Data, and Population Data

ABSTRACT

A dialysis system is provided that includes a dialysis machine and a potassium sensing device that is configured to measure the concentration of potassium in the patient&#39;s blood, in spent dialysate resulting from treating the patient, or in both. The potassium sensing device can be configured to generate a sensed value of the concentration of potassium. A control and computing unit, including a processor and a memory, is configured to receive the sensed value, compare the value with one or more values stored in the memory, and generate a control signal based on the comparison. A potassium infusion circuit uses the control signal to infuse supplemental potassium solution into the treatment dialysate, a replacement fluid, or both. The memory can include stored patient-historical and population data.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional PatentApplications Nos. 62/711,163, and 62/711,204, both filed Jul. 27, 2018,and the benefit of U.S. patent application Ser. No. ______, filed Jul.24, 2019, to Merchant et al., entitled “Method for Tailoring DialysisTreatment Based on Sensed Potassium Concentration in Blood Serum orDialysate,” each of which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to blood treatment methods that involveregulating the concentration of potassium in a patient's bloodstreamduring the treatment. The present invention also relates to prescribingtreatment parameters based on patient-historical and population data.

BACKGROUND OF THE INVENTION

Dialysis treatments are typically administered intermittently and thusfail to provide continuous waste removal as enabled by a natural,functioning kidney. After a dialysis treatment, substances such assodium and potassium salts begin to accumulate in the patient.Increasing the frequency and duration of dialysis treatments can help tomore closely resemble continuous kidney function, but the need forpatients to travel to a dialysis center, and the costs associated witheach dialysis treatment, pose limits on the frequency with whichpatients can seek dialysis treatments.

As blood potassium concentration increases between dialysis treatments,patients become more susceptible to arrhythmias and at higher risk fordeveloping hyperkalemia or sudden acute hypokalemia during dialysis.Hyperkalemia and hypokalemia increase the risk of cardiac arrhythmias.Generally, dialysis patients cannot effectively eliminate potassium fromtheir bodies so potassium must be removed during dialysis treatments.Between treatments, however, blood potassium concentrations continuallyincrease until the next treatment session. Cardiac arrhythmias includingsudden cardiac death are among common causes of death in End-Stage RenalDisease (ESRD).

Removing potassium too quickly during a dialysis treatment can also leadto complications, including shock, atrial fibrillation, cardiac arrests,and arrhythmias. Dialysis patients often experience extreme variationsin blood potassium concentrations during dialysis treatments, furtherincreasing health risks. Thus, there is a need to guard against toosudden a change in blood potassium concentration during dialysistreatments. There is also a need to manage hyperkalemia, hypokalemia,and arrhythmias in dialysis patients, during and between treatmentsessions.

SUMMARY OF THE PRESENT INVENTION

The present invention provides a dialysis system comprising a dialysismachine configured to perform a dialysis treatment on a patient, and apotassium sensing device configured to sense, measure, and/or calculatethe concentration and/or amount of potassium in at least one of thepatient's blood and spent dialysate resulting from treating the patientwith the dialysis machine. The potassium sensing device can be apotassium sensor configured to generate a measured or calculatedpotassium concentration value. A control and computing unit comprising aprocessor and a memory can control operation of the machine. The controland computing unit can receive a signal from the potassium sensingdevice and process the signal into the measured or calculated potassiumconcentration value. The processor can be configured to receive thesensed, measured, or calculated potassium concentration value, comparethe value with one or more values stored in the memory, and generate acontrol signal based on the comparison. A potassium supply system isprovided that is configured to infuse potassium into treatment dialysatethat is to be used by the dialysis machine in treating the patient. Thecontrol and computing unit can be in data transfer communication withthe potassium supply system, and the potassium supply system can beconfigured to receive the control signal and infuse a potassium solutioninto the treatment dialysate or into a replacement fluid, based on thecontrol signal. The control and computing unit can have a dataprocessing unit, for example, a microprocessor, on which a dataprocessing program, for example, software, can run.

The control and computing unit can be configured to store the measuredor calculated value of potassium concentration in the memory, forexample, to use it as historical data for future machine settings forthe patient or to use it for other patients in a patient database. Thememory can have stored therein historical patient data pertaining tomeasured or calculated potassium concentration values of the samepatient, obtained under the same and/or different patient parameters, orvalues of other patients. The different patient parameters that can bestored and used include at least one parameter based on the length oftime since a last dialysis treatment has been carried out on thepatient. An algorithm can be used that is based on inputted or looked-updata and the control signal can be based on the results of processingaccording to the algorithm.

Based on a patient's propensity to suffer from hyperkalemia,hypokalemia, or both, a kalemic constant can be assigned to the patient,for example, on a scale of from one to ten. The kalemic constant can beused to determine a line or slope defining the infusion rate ofsupplemental potassium for treating the patient over a treatment period.

Methods of treatment are also provided according to the presentinvention and can comprise using a dialysis system, as disclosed herein,and basing the treatment on patient-historical and/or population data.Records resulting from the treatment can be stored in a database ofpatient-historical and/or population data to provide more data pointsfor, and to minimize deviations of, records in the database.

Additional features and advantages of the present invention will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of thepresent invention. The objectives and other advantages of the presentinvention will be realized and attained by means of the elements andcombinations particularly pointed out in the description and appendedclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention can be even more fully understood with thereference to the accompanying drawings which are intended to illustrate,not limit, the present invention.

FIG. 1A is a schematic diagram of a dialysis system comprising anextracorporeal blood circuit, a regenerative dialysate circuit, and apotassium infusion circuit, in accordance with one or more embodimentsof the present invention.

FIGS. 1B and 1C are schematic diagrams of the electronic circuitry ofthe dialysis system shown in FIG. 1A.

FIG. 2A is a graph showing a target slope area and a prescribed slopefor the gradual reduction of blood potassium concentration in apatient's blood over the course of a dialysis treatment.

FIG. 2B is a graph showing a target slope area and a prescribed slopefor the gradual reduction of the infusion of supplemental potassium overthe course of a treatment, to achieve the reduction in blood potassiumconcentration prescribed in FIG. 2A.

FIG. 2C is a graph showing the slope of reduction of the infusion ofsupplemental potassium, to be used during a dialysis treatment, whereinthe slope is based on an area of the graph, which is defined by thelength of time since the last dialysis treatment for the patient and thepatient's historically recorded propensity to be affected by hypokalemiaresulting from a dialysis treatment.

FIG. 3 is a functional block diagram of a multi-pass sorbent-baseddialysis system including an electronic control unit, according to oneor more embodiments of the present invention.

FIG. 4 is a functional block diagram of a multi-pass sorbent-baseddialysis system, in accordance with one or more embodiments of thepresent invention.

FIG. 5 is a schematic diagram of a treatment system comprising a compactmanifold in a dialysis system, including two-way valves, to enable thecontrol of flow through blood and dialysate circuits and to select adesired mode of operation, according to one or more embodiments of thepresent invention.

FIG. 6A is a schematic diagram of a circuit forhemodialysis/hemofiltration, according to one or more embodiments of thepresent invention, and including the compact manifold shown in FIG. 5.

FIG. 6B is an exploded view of the extracorporeal blood processingsystem shown in FIG. 6A, configured to operate in hemodialysis mode.

FIG. 6C is an exploded view of an extracorporeal blood processing systemsimilar to that shown in FIGS. 6A and 6B, but configured forhemofiltration mode using a single-pass configuration and bag of freshultrapure dialysate.

FIG. 6D is a schematic diagram of a dialysate circuit including asorbent cartridge and potassium sensors, according to yet anotherembodiment of the present invention.

FIG. 7A is a cross-sectional view of a flow cell for sensing bloodpotassium concentration in blood flowing through an extracorporeal bloodcircuit.

FIG. 7B is a top view of the flow cell show in FIG. 7A.

FIG. 8 is a schematic diagram showing yet another embodiment of thepresent invention, wherein a hemodialysis device is provided that has ablood treatment unit in the form of a dialyzer or filter that is dividedinto a blood chamber and a dialysate chamber by a semipermeablemembrane, and wherein blood serum potassium concentration is regulatedby supplemental infusion of potassium ions into dialysate.

FIG. 9 is a schematic representation of an apparatus for peritonealdialysis that includes a potassium supply device comprising a syringepump driven by a stepper motor and configured to drive a supplementalsupply of potassium ions into a stream of peritoneal dialysis solution.

FIG. 10 is a representation of an apparatus for the extracorporeal bloodcirculation with a device for detecting blood serum potassium, seen in avery simplified and schematic depiction.

FIG. 11A is a representation of a partial view of a measurement unit ofan apparatus for detecting blood serum potassium with a transmitter anda receiver for detecting scattered radiation, seen in a simplifieddepiction.

FIG. 11B is a representation of a partial view of the measurement unitwith a transmitter and a receiver for detecting transmitted radiation,seen in a simplified depiction.

FIG. 11C is a representation of a partial view of an alternateembodiment of the measurement unit with a transmitter and a receiver fordetecting scattered radiation, seen in a simplified depiction.

FIG. 12 is a representation of a depiction of a principle as embodied inthe transmitting and receiving units for measuring the radiationaccording to different measuring methods.

FIG. 13 is a representation of an embodiment of a measurement apparatusfor reflection and transmission measurements.

FIG. 14 is a representation of another embodiment of a measurementapparatus for reflection and transmission measurements.

FIG. 15 is a diagram of a typical QRS-T-wave complex from an idealizedelectrocardiogram together with a schematic explanation of the negativeslope and the amplitude of the T wave, which are used to compute theratio of T wave downslope-to-amplitude (T_(S/A)) for the purpose ofestimating blood serum potassium.

FIG. 16 is a graph showing the relationship between T_(S/A) andextracellular [K⁺] (in mM) in a control group (squares) and in a groupof congenital long QT type 2 (LQT2) patients (circles).

FIGS. 17A and 17B are schematic illustrations of a fluorescent PETsensor molecule wherein a fluorophore part is responsible forfluorescence emission and the receptor is designed for a potassiumcation (K⁺), shown in absence of a targeted analyte such thatfluorescence is absent (FIG. 17A: OFF-state), and shown with an analyte(indicated by “A”) captured by the receptor such that the molecule isexcited and emits fluorescence (FIG. 17B: ON-state).

FIG. 18 is a schematic diagram showing the principle of laser inducedbreakdown spectroscopy (LIBS), whereby a tiny volume inside a dialysatestream is temporarily atomized by a focused high-energy pulsed laser,light emitted from this high-temperature spark is collected anddispersed, and the atoms present in the specimen can be identified byspecific peaks in the atomic emission spectrum.

FIG. 19 is a schematic diagram of a microfluidic optical sensor setupthat can be used according to the present invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

According to one or more embodiments, the present invention provides adialysis system comprising a dialysis machine configured to perform adialysis treatment on a patient, and a potassium sensing deviceconfigured to sense, measure, and/or calculate the amount of potassiumin at least one of the patient's blood and spent dialysate resultingfrom treating the patient with the dialysis machine. The potassiumsensing device can be a potassium sensor configured to generate ameasured or calculated potassium concentration value. A control andcomputing unit comprising a processor and a memory can control operationof the machine. The control and computing unit can receive a signal fromthe potassium sensing device and process the signal into the measured orcalculated potassium concentration value. The processor can beconfigured to receive the sensed, measured, or calculated potassiumconcentration value, compare the value with one or more values stored inthe memory, and generate a control signal based on the comparison. Apotassium supply system is provided that is configured to infusepotassium into treatment dialysate that is to be used by the dialysismachine in treating the patient. The control and computing unit can havea data processing unit, for example, a microprocessor, on which a dataprocessing program, for example, software, can run.

The control and computing unit can be in data transfer communicationwith the potassium supply system, and the potassium supply system can beconfigured to receive the control signal and infuse a potassium solutioninto the treatment dialysate or into a replacement fluid, based on thecontrol signal. The control and computing unit can be configured tostore the measured or calculated value of potassium concentration in thememory, for example, to use it as historical data for future machinesettings for the patient or to use it for other patients in a patientdatabase. The memory can have stored therein historical patient datapertaining to measured or calculated potassium concentration values ofthe same patient, obtained under the same and/or different patientparameters, or values of other patients. The different patientparameters that can be stored and used include at least one parameterbased on the length of time since a last dialysis treatment has beencarried out on the patient. An algorithm can be used that is based oninputted or looked-up data and the control signal can be based on theresults of processing according to the algorithm.

The control and computing unit can comprise an input device configuredfor inputting patient identifying information and atime-since-last-dialysis-treatment value for the patient, as well asother pertinent information or parameters. The control and computingunit can be configured to generate a control signal based on theinputted patient parameters and, for example, historical patient datastored in the memory. The memory can have stored therein historicalpopulation data pertaining to potassium concentration values of apopulation of different patients, under different patient parameters. Ofthe parameters that can be stored, used, or both, are gender, age,weight, medications, target weight loss, target weight gain, and akalemic constant for the patient. The kalemic constant can be, forexample, a scaled value of a patient's propensity to suffer fromhyperkalemia, hypokalemia, or both.

The potassium supply system can be configured to supply a concentratedpotassium infusate solution at a first rate and for a first period oftime. The dialysis machine can comprise a dialysate circuit and thedialysate circuit can be configured to use a volume of dialysate. Avalue for the first period of time can be stored in the memory, forexample, in a look-up table, and the value can be categorized in thelook-up table based on the volume of dialysate used in the dialysatecircuit. When filled, the dialysate system can comprise an amount ofdialysate equal to the volume of dialysate targeted for use in thedialysate circuit.

In one or more embodiments, the dialysis machine can comprise adialysate circuit including a sorbent cartridge, and the treatmentdialysate can comprise regenerated dialysate. Potassium infusatesolution can be added to the dialysate downstream of the sorbentcartridge, for example, directly into a post-sorbent cartridge dialysatereservoir or into dialysate circuit tubing downstream of the sorbentcartridge.

The potassium sensing device can comprise an ion selective electrode.The ion selective electrode can be mounted in or on, or housed in, aflow cell, and the flow cell can be a part of a disposableextracorporeal blood circuit tubing set. The ion selective electrode canbe a part of the flow cell, can plug into the flow cell, or both, butneed not be disposable. The ion selective electrode can comprise asensing electrode and a reference electrode pair that can be disposable,sterilizable, re-usable, or a combination thereof. The potassium sensingdevice can be configured to sense, measure, and/or calculate theconcentration of potassium in the patient's blood by using an ionselective electrode signal and/or an electrocardiogram configured togenerate signals corresponding to electrical activity of a patient'sheart.

In one or more embodiments of the present invention, a dialysis systemis provided that comprises a dialysis machine configured to perform adialysis treatment on a patient, a display, and a potassium sensingdevice configured to sense, measure, and/or calculate the concentrationof potassium in at least one of the patient's blood and spent dialysateresulting from treating the patient with the dialysis machine. Thepotassium sensing device can be configured to generate a sensed,measured, and/or calculated potassium concentration value. A control andcomputing unit can be provided that comprises a processor and a memory.The control and computing unit can have a data processing unit, forexample, a processor or microprocessor, on which a data processingprogram, for example, software, can run. The processor can be configuredto receive the sensed, measured, or calculated potassium concentrationvalue, compare the value with one or more values stored in the memory,generate a display signal based on the comparison, and optionallygenerate a control signal. The control and computing unit can be in datatransfer communication with the display and the display can beconfigured to receive the display signal and display a potassiumconcentration value. The display and display signal can be configured todisplay an indication as to whether the sensed, measured, or calculatedvalue of potassium concentration is too high, too low, or within anacceptable range. The potassium sensing device can be configured tosense, measure, and/or calculate the concentration of potassium in thepatient's blood and can comprise an electrocardiogram configured togenerate signals corresponding to electrical activity of the patient'sheart, for example, as described in U.S. Pat. No. 9,561,316 B2 to Gerberet al. and U.S. Pat. No. 9,456,755 B2 to Soykan et al. and U.S. PatentApplication Publication No. US 2017/0000936 A1 to Soykan et al., each ofwhich is incorporated herein in its entirety by reference.

FIG. 1A is a flow path diagram for a hemodialysis machine comprising adialysate circuit 50 and an extracorporeal blood circuit 80. Dialysatecircuit 50 includes a sorbent cartridge 52 for regenerating useddialysate. A first dialysate pump 54 and a second dialysate pump 56circulate dialysate through dialysate circuit 50 including through thedialysate-side of a dialyzer 60. The pump can move the dialysate throughsorbent cartridge 52, into a dialysate reservoir 62, out of dialysatereservoir 62, and back through dialyzer 60. Downstream of dialysatereservoir 62, but upstream of second dialysate pump 56, and electrolytesinfusion line 64 merges with the dialysate circuit so that electrolytes,for example, that may have been removed from the dialysate, by sorbentcartridge 52, can be replenished or replaced and thus available fortransfer, through dialyzer 60, into extracorporeal blood circuit 80.Electrolytes infusion line 64 is part of an electrolytes circuit 65 thatalso includes an electrolytes container 66, a container level sensor 67,and an electrolytes pump 68. Electrolytes pump 68 is configured to movea concentrated electrolytes solution from electrolytes container 66through electrolytes infusion line 64 and into the dialysate tubing ofdialysate circuit 50, between dialysate reservoir 62 and seconddialysate pump 56.

A potassium infusion circuit 165 separately provides for the controlledinfusion of potassium into the dialysate tubing of dialysate circuit 50.A potassium infusion line 164 merges with dialysate circuit 50downstream of sorbent cartridge 52 and downstream of dialysate reservoir62, but upstream of second dialysate pump 56 and upstream of dialyzer60. Potassium infusion circuit 165 comprises a potassium solutioncontainer 166 and a potassium infusate pump 168 configured to move aconcentrated potassium infusate solution from potassium solutioncontainer 166 and through potassium infusion line 164. The level ofpotassium infusate solution can be monitored via a level detector 167and the amount and rate of potassium infused can thus be measured,calculated, or both.

Dialysate circuit 50 is also provided with a fill and drain valve 70, abypass IN valve 71, and a bypass OUT valve 72. The valves enable fillingof dialysate circuit 50 with dialysate from a jug or other source,through a fill and drain port 73, and draining of dialysate circuit 50through fill and drain port 73. When fill and drain valve 70 is closed,dialysate can neither be filled into nor drained from dialysate circuit50.

With dialysate fill and drain valve 70 in a closed position, bypass INvalve 71 and bypass OUT valve 72 can be operated to enable circulationof dialysate through dialysate circuit 50 with or without bypassing flowthrough dialyzer 60. Bypassing can be useful, for example, for priming,filling, and draining dialysate circuit 50. Pressure sensors 74, 75, and76 are used to monitor the pressure in dialysate circuit 50 and can beused to control the pump speed of one or both of first dialysate pump 54and second dialysate pump 56. Dialysate circuit 50 also comprises anammonium sensor 77 adjacent to, and downstream from, sorbent cartridge52 and upstream of dialysate reservoir 62.

Dialysate reservoir 62 can rest on or be suspended from a scale 61 and,through scale 61, or independent of scale 61, can be in thermal contactwith a heater and thermistor unit 63 that comprises a heater and athermistor, thermometer, or other temperature sensing device. A scale 53can also be provided for weighing sorbent cartridge 52. Based on thecombined weight detected by reservoir scale 61 and sorbent cartridgescale 52, and based on known volumes of the tubing and dialyzer ofdialysate circuit 50, the volume, weight, or other amount of dialysatein dialysate circuit 50 can be determined, monitored, and controlled soas to pull fluid off of a patient, infuse a certain amount of dialysateinto a patient, or maintain a certain patient weight.

Dialysate circuit 50 can also comprise, or pass-through, a blood leaksensor 78 adjacent to and immediately downstream of dialyzer 60, tosense the presence of blood in the dialysate. Blood leak sensor 78 cancomprise, for example, an optical blood leak sensor.

Extracorporeal blood circuit 80 comprises a to-patient connector 81 atthe end of a venous return line 82, a from-patient connector 83 at anend of an arterial line 84, and the blood-side of dialyzer 60. A bloodpump 85 is configured to pull blood from a patient through arterial line84 and push the blood through dialyzer 60 and back to the patientthrough venous return line 82. A blood flow IN pressure sensor 86 isprovided along blood circuit 80 downstream of blood pump 85 but upstreamof dialyzer 60. A blood flow OUT pressure sensor 88 is proved alongblood circuit 80 downstream of dialyzer 60, along venous return line 82.An air bubble sensor 90 and a pinch valve 92 are also provided alongvenous return line 82. Control electronics are provided such that, inthe event that air bubble sensor 90 senses air in venous return line 82,a control signal is sent to pinch valve 92 to pinch-shut venous returnline 82 and prevent the air from entering the patient's bloodstream.

Along arterial line 84 are provided an occlusion detector 94, and aconnection to a saline supply line 96. For the connection, aT-connector, Y-connector, two-way valve, or the like, can be used. Asaline bag 98 supplies saline, and optionally anticoagulant, to salinesupply line 96. A medicine part (not shown) can be provided along salinesupply line 96.

In accordance with the present teachings, extracorporeal blood circuit80 can comprise a first potassium sensor 100 along arterial line 84upstream of the connection to saline supply line 96, and a secondpotassium sensor 102 along venous return line 82. While two sensors areshown and described, it is to be understood that it is possible to useonly one of the first and second potassium sensors, or both. The use ofjust a single potassium sensor, along either arterial line 84 or venousreturn line 82, can be implemented and is still within the spirit andscope of the present teachings. Control signals generated by one or bothof first and second potassium sensors 100 and 102 can be sent over wiredor wireless communication lines and used by a processor to control theoperation and speed of potassium pump 168 so that the concentration ofpotassium in the dialysate can be carefully controlled. The carefulcontrol can provide a slow and gradual reduction in potassium bloodlevel concentration such that the patient will neither be subject to norfeel the effects of sudden drastic changes in potassium concentrationsduring treatment.

As shown in FIG. 1B, each of the pumps, valves, sensors, and detectorsshown corresponds to the respective pumps, valves, sensors, anddetectors described in connection with FIG. 1A, and identical referencenumbers refer to identical components. As can be seen in FIG. 1B, eachof the pumps, valves, sensors, and detectors is provided with a controlline for sending signals to and/or receiving control signals from acontrol unit 1000 as shown in FIG. 1C. The control unit can have a dataprocessing unit, for example, a processor or microprocessor, on which adata processing program, for example, software, can run. Each of thecontrol lines has been designated using the same reference numeral asthe component to which it is connected, but with an added apostrophe orprime (′) notation so as to be distinguished from its correspondingcomponent. While the various control lines are shown with arrow headsleading away from the corresponding components in FIG. 1B, and towardscontrol unit 1000 in FIG. 1C, it is to be understand that the controllines can be for sending and/or receiving signals to and/or from controlunit 1000. Each of the control lines can independently comprise a wire,cable, coaxial cable, harness, trace, or other electrically conductivelead, but it is also to be understood that signals can be sent to andfrom the various components and to and from control unit 1000wirelessly, for example, using Wi-Fi or Bluetooth technologies, or thelike.

A memory 1002 can be a part of or independent from control unit 1000 andcan be in data transfer communication, with control unit 1000 orcomponents thereof. As shown in FIG. 1C, a data transfer line 1004connects control unit 1000 to memory 1002 so that data can be sent fromcontrol unit 1000 to be stored in memory 1002 and data can be retrievedfrom memory 1002 to be used by control unit 1000. Memory 1002 cancomprise a read-write memory such that data acquired by control unit1000 via the various sensors and detectors can be stored in memory 1002and can be used during a current or future treatment session or toprovide data to a patient historical database, a patient populationdatabase, or the like.

Control unit 1000 can comprise a processor, microprocessor, centralprocessing unit (CPU), computer, or other processing device. Controlunit 1000 can comprise multiple processors, a comparator, a regulator,logic circuitry, and the like components as would be recognized by thoseof skill in the art. Control unit 1000 can be a component of a centralcontrol unit of the treatment device. The central control unit can havea data processing unit, for example, a microprocessor, on which a dataprocessing program, for example, software, can run.

As shown in FIGS. 1B and 1C, pumps 54, 56, 68, 85, and 168 are connectedby means of control lines 54′, 56′, 68′, 85′, and 168′, respectively, tocontrol unit 1000. Valves 70, 71, and 72 are configured to receivecontrol signals from control unit 1000 via control lines 70′, 71′, and72′, respectively. Pinch-valve 92 is configured to receive controlsignals from control unit 1000 via control line 92′. Control unit 1000is configured to receive pressure signals from pressure sensors 74, 75,76, 86, and 88, via control lines 74′, 75′, 76′, 86′, and 88′,respectively. Control of the various pumps and valves can be based onpressure signals received from the pressure sensors as well as based onsensed and detected conditions, acquired by the other various sensorsand detectors, which are sent to control unit 1000 over respectivecontrol lines. Potassium concentration sensors 100 and 102 areconfigured to send potassium concentration signals to control unit 1000via control lines 100′ and 102′, respectively. An air bubble sensorsignal can be sent to control unit 1000 from air bubble sensor 90 viacontrol line 90′. A blood leak sensor signal can be sent from blood leaksensor 78 to control unit 1000 via control line 78′. An occlusiondetector signal can be sent from occlusion detector 94 to control unit1000 via control line 94′. An ammonia sensor signal can be sent fromammonia sensor 77 to control unit 1000 via control line 77′.

The level of concentrated electrolytes solution in electrolytescontainer 66 can be sensed by level sensor 67 and a signal correspondingto the sensed level can be sent to control unit 1000 via control line67′. The level of concentrated potassium infusate solution in container166 can be sensed by level sensor 167 and a signal corresponding to thesensed level can be sent from level sensor 167 to control unit 1000 viacontrol line 167′.

Control unit 1000 can be configured to take into account the potassiumconcentrations sensed by potassium sensor 100, potassium sensor 102, orboth, in determining whether, and how much, supplemental potassiumshould be pumped into the dialysate circuit via potassium infusioncircuit 165. Control unit 1000 is configured, in response to the signalsreceived, to send a control signal to the potassium infusate pump 168via control line 168′ to control infusion of supplemental potassium soas to achieve a prescribed potassium concentration in the dialysate, theblood, or both. The level of concentrated potassium infusate solutionsensed by level sensor 167 can be sent as a signal via control line 167′to control unit 1000 so that the amount of supplemental potassiuminfused can be carefully controlled and regulated. Although FIGS. 1A-1Cdepict two potassium concentration sensors along blood circuit 80, it isto be understand that potassium concentration sensors can additionally,or instead, be provided along dialysate circuit 50 and the control ofpotassium concentration in a dialysate can be used to control, predict,estimate, and/or extrapolate the concentration of potassium in apatient's blood.

For detecting the concentration of potassium in a patient's blood, oneor more potassium concentration sensors can be implemented in theextracorporeal blood circuit. Many devices and systems are known tothose skilled in the art and can be implemented in accordance with thepresent teachings. Chemical sensors that have heretofore been implantedin a patient can be incorporated into an extracorporeal blood circuit asif the circuit were a part of the human anatomy. In this regard, theextracorporeal blood circuit can include a flow cell wherein anotherwise implantable medical device can be mounted or contacted in aconfiguration that enables sensing of potassium in blood flowing throughthe flow cell in the extracorporeal blood circuit. An exemplaryimplantable medical device for such a purpose can, for example, be adevice as described in U.S. Pat. No. 8,571,659 B2 to Kane et al., whichis incorporated herein in its entirety by reference. Another sensor thatcan be implemented and incorporated into an extracorporeal blood circuitis one or more of the devices described in U.S. Pat. No. 9,510,780 B2 toSilver, which is incorporated herein in its entirety by reference. Anyof a wide variety of ion selective electrodes can also be used, forexample, mounted in or on a flow cell included as a component of theextracorporeal blood circuit. The flow cell can be configured as adisposable component and the ion selective electrode or other potassiumsensor device can be plugged into the flow cell, disconnected after use,and sterilized for reuse. In other words, the potassium sensor need notbe a disposable component but can, if desired, be configured as a partof the extracorporeal blood circuit disposable tubing system.

Exemplary potassium sensors comprising ion selective electrodes includethose described in U.S. Pat. No. 9,377,429 B2 to Iwamoto, U.S. Pat. No.9,297,797 B2 to Situ et al., U.S. Pat. No. 8,765,060 B2 to Buhlmann etal., U.S. Pat. No. 7,790,112 B2 to Vanaja et al., U.S. Pat. No.7,373,195 B2 to Ye, U.S. Pat. No. 7,368,231 B2 to Yuan, U.S. Pat. No.6,432,296 B1 to Daniel et al., U.S. Pat. No. 5,964,994 to Craig et al.,U.S. Pat. No. 4,902,399 to Durley, III et al., U.S. Pat. No. 4,892,640to Wolfbeis et al., U.S. Pat. No. 4,814,060 to Banks, U.S. Pat. No.4,535,786 to Kater, U.S. Pat. No. 4,461,998 to Kater, U.S. Pat. No.4,361,473 to Young et al., U.S. Pat. No. 4,340,457 to Kater, U.S. Pat.No. 4,276,141 to Hawkins, U.S. Pat. No. 3,856,649 to Genshaw et al., andU.S. Pat. No. 3,598,713 to Baum et al. Other exemplary potassium sensorscomprising ion selective electrodes include those described in U.S.Patent Application Publications Nos. US 2016/0195491 A1 to Rao, US2015/0008122 A1 to Thompson, US 2014/0174923 A1 to Rao, US 2013/0168247A1 to Iwamoto, US 2012/0261260 A1 to Li et al., US 2012/0175254 A1 toKobayashi et al., US 2012/0175253 A1 to Kobayashi et al., US2010/0252429 A1 to Rao, and US 2008/0264790 A1 to Kamahori et al. Eachof the patents and published applications mentioned herein isincorporated by reference herein, in its entirety.

Signals corresponding to sensed potassium concentrations can be sent toa control unit to be used in an algorithm designed to provide a targetprescription for the infusion of supplemental potassium into a dialysatecircuit used for dialyzing blood in the extracorporeal blood circuit.The control unit can have a data processing unit, for example, aprocessor or microprocessor, on which a data processing program, forexample, software, can run.

In an exemplary method using an exemplary system, a goal can be set toreduce potassium concentration in a patient, within a certain,prescribed, or otherwise set, time of treatment. The goal can be areduction in potassium concentration such that the concentration ends upbeing within a certain range or ends up crossing a certain threshold.Range and threshold values can be inputted according to a prescription.The range or threshold can be from 1.5 mEq/L to 4.0 mEq/L, from 1.75mEq/L to 3.5 mEq/L, from 2.0 mEq/L to 3.25 mEq/L, or from 2.0 mEq/L to2.5 mEq/L. An endpoint concentration can be set using an input pad,screen, or keyboard, or can be automatically set from a downloaded orotherwise input prescription. Once the target or inputted concentrationis attained, as measured by one or more potassium sensors, the deliveryof any supplemental potassium via a potassium infusion circuit can beceased.

To achieve such a reduction in potassium concentration most safely for apatient, a gradual reduction in potassium concentration, over themajority of a treatment session, can be achieved by infusing aconcentrated, supplemental supply of potassium to a dialysate circuit.The concentrated, supplemental supply of potassium can be infusedupstream of a dialyzer in a single-pass hemodialysis system. Theconcentrated, supplemental supply of potassium can be infused upstreamof a dialyzer and downstream of a sorbent or regenerative cartridge in amulti-pass hemodialysis system. Instead, or in addition, a supplementalsupply of potassium can be added to a substituate or replacement fluid,to enable pre-dilution, post-dilution, or both, in a hemodiafiltrationsystem. By “supplemental potassium” what is meant is that the potassiumis supplemental to any potassium that is otherwise already added to adialysate or replacement fluid from an electrolyte or infusate mix thatmight also contain sodium, calcium, magnesium, bicarbonate, and thelike, well-known components used in the preparation, replenishment, andmaintenance of dialysate. Such an electrolytes mix can be infused by anelectrolytes infusion circuit as described herein.

FIG. 2A is a graph showing an area of target slope for reducing theconcentration of potassium in a patient over the course of a bloodtreatment. A prescription, for example, based on an algorithm asdescribed herein, can be downloaded or otherwise inputted into a centralprocessor of a blood treatment system. Using signals received frompotassium concentration sensors, the central processor can send controlsignals to a potassium infusion circuit so that a supplemental supply ofconcentrated potassium can be infused into a dialysate or replacementfluid used by the blood treatment system. Infusion can be controlledsuch that the amount of potassium to be infused can be calculated toenable a gradual decrease in potassium concentration over a good part ofor an entire treatment session, for example, over the entire four-hourtreatment session exemplified in FIGS. 2A and 2B.

In FIG. 2B, a graph is shown depicting the rate of supplementalpotassium infusion over the same four-hour treatment period shown inFIG. 2A. To achieve the goal or target slope illustrated in FIG. 2A,that is based on an inputted prescription including the target slopeshown in FIG. 2A, a gradual reduction in a rate of supplementalpotassium infusion, as shown in FIG. 2B, can be enabled by the system.Potassium sensing before and after treatments can be used by thealgorithm, for example, as data points, to further and better definetarget zones of slope, target rates of change, and target reductions ofinfusion rates, and to build a multi-dimensional database of results.Such a multi-dimensional database can be useful to define an optimumtreatment prescription for a particular patient under a particular setof conditions.

Each of the prescription slopes shown in FIGS. 2A and 2B can beprescribed by a physician based on any number of factors, differentconditions, historical data of the patient, population data, or thelike. One exemplary method that a physician can use to prescribe a slopefor the gradual reduction of supplemental potassium infusion involvesapplying knowledge of the patient's propensity or likelihood to beaffected by hypokalemia, deduced from analysis of historical dialysistreatments on the patient. While evaluating the effects of hypokalemiacan be subjective, a physician or clinician can evaluate physiologicalproperties and/or conditions of the patient after each of a plurality ofdialysis treatments. The patient's input such as answers to questionsand replies to inquiries can be useful in evaluating the patient and theeffects of the treatment. Blood pressure, heart beat rate, and potassiumblood test results can be evaluated. The evaluator can then scale thepatient's propensity to be affected by hypokalemia, based on theevaluation. The patient's propensity to suffer or to be affected can,for example, be scaled on a scale of from 0 (zero) to 10 (ten).

As shown in FIG. 2C, a graphical representation of the patient's scaledpropensity to be affected by hypokalemia can be coordinated with thetime since the patient last received a dialysis treatment, and thecoordinate can be plotted on the graph. Depending upon which area of thegraph the plotted coordinate lands, the physician can prescribe thecorresponding suggested slope for gradually reducing the infusion ofsupplemental potassium over the course of the next treatment.

As shown in FIG. 2C, the physician may prescribe a very gradual slopefor the reduction of supplemental potassium infusion, for any patientthat has gone more than sixty (60) hours since his or her last dialysistreatment. For patients that have been evaluated and are determined tohave a very low propensity to be affected by hypokalemia, and that havegone less than sixty (60) hours since their last dialysis treatment, amore aggressive or steeper negative slope can be prescribed to morerapidly decrease the infusion of supplemental potassium during the nextdialysis treatment.

Although FIG. 2C shows the scaled propensity and the time since lasttreatment as a graphical representation, it is also to be understoodthat such data could be represented in a look-up table that is printedout or stored in a computer memory, arranged on a spreadsheet printedout or stored in a computer memory, stored in an external drive, storedon a readable medium, a combination thereof, or the like.

The system shown in FIGS. 1A and 1B is exemplary of a multi-passdialysate regeneration system according to one or more embodiments ofthe present teachings. The disclosed embodiments can be used to providedialysis treatments to a patient. FIG. 3 is a functional block diagramof another multiple-pass sorbent-based dialysis system according to oneor more embodiments of the present invention, but which could also beconfigured as a single-pass system using one or more bags of freshdialysate. Dialysis system 2600 employs a dialyzer cartridge 2602comprising a high flux membrane to remove toxins from the blood both bydiffusion and by convection. The removal of toxins by diffusion isaccomplished by establishing a concentration gradient across thesemi-permeable membrane by allowing a dialysate solution to flow on oneside of the membrane in one direction while simultaneously allowingblood to flow on the other side of the membrane in opposite direction.To enhance removal of toxins using hemodiafiltration, a substitutionfluid is continuously added to the blood either prior to the dialyzercartridge (pre-dilution) or after the dialyzer cartridge(post-dilution). An amount of fluid equal to that of the addedsubstitution fluid is “ultra-filtered” across the dialyzer cartridgemembrane, carrying the added solutes with it.

Referring to both FIGS. 3 and 4 simultaneously, blood containing toxinscan be pumped from a blood vessel of a patient by a blood pump 2601,2701 and transferred to flow through dialyzer cartridge 2602, 2702.Optionally, inlet and outlet pressure sensors 2603, 2604, 2703, 2704 inthe blood circuit can be used to measure the pressure of blood bothbefore it enters the dialyzer cartridge 2602, 2702 via the blood inlettube 2605, 2705 and after leaving the dialyzer cartridge 2602, 2702 viathe blood outlet tube 2606, 2706. Pressure readings from sensors 2603,2604, 2628, 2703, 2704, 2728 are used as a monitoring and controlparameter of the blood flow. A potassium sensor as disclosed herein isarranged in the form of a flow cell 2619. A patient's blood potassiumconcentration can be sensed, measured, and/or calculated by the sensor,for example, via processing by an electronic control unit 2616.Electronic control unit 2616 has a data processing unit in the form of amicroprocessor, on which a data processing program (software) can run. Aflow meter 2621, 2721 may be interposed in, or otherwise in pressurecommunication with, the portion of blood inlet tube 2605, 2705 that islocated directly upstream from the blood pump 2601, 2701. The flow meter2621, 2721 is positioned to monitor and maintain a predetermined rate offlow of blood in the impure blood supply line. A substitution fluid 2690may be continuously added to the blood either prior to the dialyzercartridge (pre-dilution) or after the dialyzer cartridge(post-dilution). The substitution fluid can comprise a solution ofsupplemental potassium, for example, consisting essentially of potassiumin solution and being free of other minerals.

In both FIGS. 3 and 4, dialyzer cartridge 2602, 2702 comprises asemi-permeable membrane 2608, 2708 that divides the dialyzer 2602, 2702into a blood chamber 2609, 2709 and a dialysate chamber 2611, 2711. Asblood passes through the blood chamber 2609, 2709, uremic toxins arefiltered across the semi-permeable membrane 2608, 2708 due to convectiveforces. According to one or more embodiments, additional blood toxinsare transferred across the semi-permeable membrane 2608, 2708 bydiffusion, primarily induced by a difference in concentration of thefluids flowing through the blood and dialysate chambers 2609, 2709 and2611, 2711 respectively. The dialyzer cartridge used may be of any typesuitable for hemodialysis, hemodiafiltration, hemofiltration, orhemoconcentration, as are known in the art. In one embodiment, thedialyzer 2602, 2702 contains a high flux membrane. Examples of suitabledialyzer cartridges include, but are not limited to, Fresenius® F60, F80available from Fresenius Medical Care of Lexington, Mass., Baxter Conn.110, CT 190, Syntra® 160 available from Baxter of Deerfield, Ill., orMinntech Hemocor HPH® 1000, Primus® 1350, 2000 available from Minntechof Minneapolis, Minn.

Dialysate pump 2607, 2707 can draw spent dialysate from the dialyzercartridge 2602, 2702 and force the dialysate into a dialysateregeneration system 2610, 2710 and back into the dialyzer cartridge2602, 2702 in a multiple pass loop, thus generating “re-generated” orfresh dialysate. Optionally, a flow meter 2622, 2722 can be interposedin the spent dialysate supply tube 2612, 2712, 2613, 2713 upstream fromdialysate pump 2607, 2707, which monitors and maintains a predeterminedrate of flow of dialysate. A blood leak sensor 2623, 2723 can also beinterposed in spent dialysate supply tube 2612, 2712.

The multi-pass dialysate regeneration system 2600, 2700 of the presentinvention comprises a plurality of cartridges and/or filters containingsorbents for regenerating the spent dialysate. By regenerating thedialysate with sorbent cartridges, the dialysis system 2600, 2700 of thepresent invention requires only a small fraction of the amount ofdialysate of a conventional single-pass hemodialysis device.

In one embodiment, each sorbent cartridge in the dialysate regenerationsystem 2610, 2710 is a miniaturized cartridge containing a distinctsorbent. For example, the dialysate regeneration system 2610, 2710 mayemploy five sorbent cartridges, wherein each cartridge separatelycontains activated charcoal, urease, zirconium phosphate, hydrouszirconium oxide and activated carbon. In another embodiment eachcartridge can comprise a plurality of layers of sorbents described aboveand there can be a plurality of such separate layered cartridgesconnected to each other in series or parallel in the dialysateregeneration system. Persons of ordinary skill in the art wouldappreciate that activated charcoal, urease, zirconium phosphate, hydrouszirconium oxide and activated carbon are not the only chemicals that canbe used as sorbents in the present invention. In fact, any number ofadditional or alternative sorbents, including polymer-based sorbents,can be employed without departing from the scope of the presentinvention.

While the current embodiment has separate pumps 2601, 2701, 2607, 2707for pumping blood and dialysate through the dialyzer, in an alternateembodiment, a single dual-channel pulsatile pump that propels both bloodand dialysate through the hemodiafiltration system 2600, 2700 can beemployed. Additionally, centrifugal, gear, or bladder pumps can be used.

In one or more embodiments, supplemental potassium can be added to thedialysate in the dialysate tube 2613, 2713 using a volumetric micro-pump2614, 2714 to increase the amount of potassium in the regenerateddialysate. The addition of supplemental potassium can be controlled by amicropump control signal generated by electric control unit 2616, forexample, according to an input prescription. Supplemental potassium canbe supplied from a solution reservoir 2615, 2715 that can beperiodically refilled, as needed, via an inlet. A level sensor can beprovided to monitor the amount of potassium solution that has beeninfused into the dialysate. The supplemental potassium solution can be aconcentrated solution of potassium in water, for example, a solution ofK⁺Cl⁻ in otherwise deionized water. Solutions having a potassiumconcentration of from about 300 milligrams per Liter (mg/L) to about2,500 mg/L can be used, or solutions having concentrations of from 500mg/L to 2,000 mg/L, or from 700 mg/L to 1,500 mg/L, or from 900 mg/L to1,200 mg/L, or having a concentration of 1,000 mg/L. Supplementalpotassium solutions having these concentrations of potassium, when addedto dialysate at rates of from about one mL per minute to about 100 mLper minute, for example, from 10 mL per minute to 60 mL per minute, orfrom 20 mL per minute to 50 mL per minute, can supplement and increasethe potassium concentration in the dialysate and thus provide ormaintain relatively higher blood serum potassium concentrations duringdialysis. Such relatively higher blood serum potassium concentrationscan be useful, at least at the beginning of a dialysis treatment, tominimize the potential for hypokalemia developing in the patient,resulting from the dialysis.

The potassium concentration of the dialysate entering a dialyzer can becontrolled by a combination of controlling the supplemental potassiumsolution concentration and controlling the rate of addition or infusionof the supplemental potassium solution into the dialysate stream. Asmentioned above, electronic control unit 2616 comprises a microprocessorand monitors and controls the functionality of all components of thesystem 2600.

In one embodiment, dia-filtered blood exiting dialyzer cartridge 2602,2702 is mixed with regulated volumes of sterile substitution fluid thatis pumped into the blood outlet tube 2606, 2706 from a substitutionfluid container 2617, 2717 via a volumetric micro-pump 2618, 2718.Substitution fluid is typically available as a sterile/non-pyrogenicfluid contained in flexible bags. This fluid can also be producedon-line by filtration of a non-sterile dialysate through a suitablefilter cartridge rendering it sterile and non-pyrogenic.

To enable a control flow through the blood and dialysate circuits and toselect the desired mode of operation (hemodialysis or hemofiltration),the system can be provided with two-way valves, as described above.These valves can be actuated by a user to direct dialysate flow eitherthrough the dialyzer in one mode of operation or to deliver infusategrade dialysate flow directly to a patient, in a second mode ofoperation. These two-way valves can also be integrated with the compactmanifold of the dialysis circuit. This is illustrated in FIG. 5. Itshould be noted that in FIGS. 5 and 6A-6C, for the purpose of clarity,corresponding elements are labelled with the same reference numerals.

Referring to FIG. 5, extracorporeal blood processing system 6800comprises a plastic molded compact manifold 6810 that encapsulates aplurality of molded blood and dialysate fluidic paths as well as aplurality of sensor areas, valves and fluidic pump segments. Dialyzer6805, when connected to the arterial blood tube 6801 and venous bloodtube 6802 of manifold 6810, completes the blood circuit of system 6800.In one embodiment, dialyzer 6805 is disposable. Two lines, 6803 and6804, are used for circulating spent and fresh dialysate respectively.For operating system 6800 in either of the two modes (hemodialysis andhemofiltration), a two-way valve 6845, and a backup two-way valve 6846are provided. Back up valve 6846 is employed because the dialysate usedin hemodialysis is not sterile and not infusion grade while the fluidused in hemofiltration is. If operating in hemodialysis mode or if thereis a leak or other failure of valve 6845, valve 6846 provides doubleprotection against that fluid being pumped into the patient bloodstream. Inclusion of backup valve 6846 allows the use of one manifoldfor both hemodialysis and hemofiltration safely. As noted above, two-wayvalves such as backup valve 6846 are composed of two single valves. Inthis case both one-way valves are in series and so by closing both portsof two-way valve 6846 double protection is afforded preventing dialysatefrom entering the blood stream. In an alternate embodiment a manifoldcan be made that is only intended for hemodialysis, having no connectionbetween dialysis fluid circuit and blood circuit, thereby permittingvalve 6846 to be safely eliminated.

Depending upon the patient's requirements, for example, as prescribed bya physician's prescription, desired quantities of concentrated potassiuminfusate solution from the potassium infusate container 6850 can bepumped, pulled, gravity-fed, or otherwise moved into the dialysatecircuit passing through manifold 6810 so as to be added to the dialysatein the dialysate circuit. The concentrated potassium infusate solutioncan be a sterile solution that helps maintain a desired concentration ofpotassium in the dialysate, for example, at a level prescribed by aphysician. A bypass valve and peristaltic pump, for example, can beprovided to select the desired amount of concentrated potassium infusatesolution and to ensure proper flow of the solution into the dialysate.Similarly, and depending upon a patient's requirements, as, for example,prescribed by a physician, a desired quantity of concentratedelectrolytes solution from an electrolytes container 6851 can be pumped,pulled, gravity-fed, or otherwise moved into the dialysate circuit inmanifold 6810. The concentrated electrolytes solution can be a sterilesolution containing minerals, glucose, or the like, to help maintainminerals, including calcium and magnesium, in the dialysate at levelsprescribed by a physician. The concentrated electrolytes solution canalso contain potassium, but at a desired end-point concentration.Accordingly, dosing supplemental potassium such that an elevatedconcentration can be gradually reduced to a desired end-pointconcentration, can be enabled in accordance with the present teachings.A bypass valve and peristaltic pump can be provided to select thedesired amount of concentrated electrolytes solution and to ensureproper flow of the solution into the dialysate. Through appropriatevalving and plumbing, either or both the concentrated potassium infusatesolution and the concentrated electrolytes solution can be pulled intothe dialysate circuit from a single, common pump, for example, aperistaltic pump. The system comprises a control and computing unit thathas a data processing unit, for example, a microprocessor, on which adata processing program (software) can run.

FIG. 6A illustrates an exemplary circuit for ahemodialysis/hemofiltration system according to one or more embodimentsof the present invention. Spent dialysate and fresh dialysate tubes 6903and 6904, respectively, are connected to a dialysate regeneration system6906 thereby completing the dialysate circuit of the system 6900. Thedialysate regeneration system 6906 further comprises disposable sorbentcartridges 6915 and a reservoir 6934 to hold dialysate cleansed bycartridges 6915. Other components of the system shown in FIG. 6A areexplained with reference to FIG. 6B, which shows an exploded view of theextracorporeal blood processing system 6900 configured to operate inhemodialysis mode. Corresponding elements in FIGS. 6A, 6B, and 6C havethe same numbers.

Blood circuit 6920 comprises a peristaltic blood pump 6921 (FIGS. 6B and6C) that draws a patient's arterial impure blood along the tube 6901 andpumps the blood through dialyzer 6905. A syringe device 6907 injects ananticoagulant, such as heparin, into the drawn impure blood stream.Pressure sensor 6908 is placed at the inlet of the blood pump 6921 whilepressure sensors 6909 and 6911 are placed upstream and downstream of thedialyzer 6905 to monitor pressure at these vantage points.

As purified blood flows downstream from the dialyzer 6905 and back tothe patient, a blood temperature sensor 6912 is provided in the line tokeep track of temperature of the purified blood. An air eliminator 6913is also provided to remove accumulated gas bubbles in the clean bloodfrom the dialyzer. A pair of air (bubble) sensors (or optionally asingle sensor) 6914 and a pinch valve 6916 are employed in the circuitto prevent accumulated gas from being returned to the patient.

The dialysate circuit 6925 comprises two dual-channel pulsatiledialysate pumps 6926, 6927. Dialysate pumps 6926, 6927 draw spentdialysate solution from the dialyzer 6905 and the regenerated dialysatesolution from reservoir 6934 respectively. At the point where useddialysate fluid from the dialyzer 6905 enters the dialysate circuit6925, a blood leak sensor 6928 is provided to sense and prevent anyleakage of blood into the dialysate circuit. Spent dialysate from theoutlet of the dialyzer 6905 then passes through the bypass valve 6929 toreach two-way valve 6930. A pressure sensor 6931 is placed between thevalves 6929 and 6930. An ultrafiltrate pump 6932 is provided in thedialysate circuit, which is operated periodically to draw ultrafiltratewaste from the spent dialysate and store it in an ultrafiltrate bag6933, which is emptied periodically.

As mentioned previously, spent dialysate is regenerated using sorbentcartridges. The dialysate regenerated by means of sorbent cartridge 6915is collected in a reservoir 6934. Reservoir 6934 includes conductivityand ammonia sensors 6961 and 6962 respectively. From reservoir 6934,regenerated dialysate passes through flow restrictor 6935 and pressuresensor 6936 to reach a two-way valve 6937. Depending upon a patient'srequirements, desired quantities of concentrated potassium infusatesolution from container 6950 and/or concentrated electrolytes solutionfrom container 6951 can be added to the dialysate. The concentratedpotassium infusate solution is a sterile solution of potassium that, bya controlled infusion, helps initially maintain potassium in thedialysate at concentrations prescribed by a physician. The concentratedelectrolytes solution is a sterile solution containing minerals and/orglucose that help maintain minerals like calcium and magnesium in thedialysate at levels prescribed by a physician. A bypass valve 6941 and aperistaltic pump 6942 are provided to select the desired amount ofconcentrated potassium infusate solution and concentrated electrolytessolution, and to ensure proper flow of the solutions into cleanseddialysate emanating from reservoir 6934.

The dialysate circuit comprises two two-way valves 6930 and 6937. Valve6930 directs one stream of spent dialysate to a first channel ofdialysate pump 6926 and another stream of spent dialysate to a firstchannel of dialysate pump 6927. Similarly, valve 6937 directs one streamof regenerated dialysate to a second channel of dialysate pump 6926 andanother stream of regenerated dialysate to a second channel of dialysatepump 6927.

Streams of spent dialysate from pumps 6926 and 6927 are collected bytwo-way valve 6938 while streams of regenerated dialysate from pumps6926 and 6927 are collected by two-way valve 6939. Valve 6938 combinesthe two streams of spent dialysate into a single stream that is pumpedvia pressure sensor 6940 and through sorbent cartridges 6915 where thespent dialysate is cleansed and filtered before being collected inreservoir 6934. Valve 6939 combines the two streams of regenerateddialysate into a single stream, which flows to two-way valve 6945through a bypass valve 6947. A pressure sensor 6943 and a dialysatetemperature sensor 6944 are provided on the dialysate flow stream totwo-way valve 6945.

By reversing the state of two-way valves 6930, 6937, 6938 and 6939,pumps 6926 and 6927 are reversed in their action of one withdrawingdialysis fluid from dialyzer 6905 and the other supplying dialysis fluidto dialyzer 6905. Such reversal, when done periodically over shortperiods of time relative to the dialysis session, ensures that over thelonger period of the entire dialysis session the dialysate fluid volumepumped into the dialyzer equals the amount of fluid pumped out and theonly total fluid volume lost by dialysis circuit 6925 is that removed byultrafiltrate pump 6932.

In hemodialysis mode, two-way valve 6945 allows the regenerateddialysate to enter dialyzer 6905 to enable normal hemodialysis of thepatient's blood. One side of valve 6945 is closed leading to thepatient's blood return line. Another two-way valve 6946 acts as abackup, keeping dialysate from entering the patient's blood line, withboth ports of valve 6946 closed even if valve 6945 leaks or fails.

Referring to FIG. 6C, in hemofiltration mode, two-way valve 6945 can beactuated to direct a stream of fresh ultrapure dialysate from reservoir6952 through valve 6946, now with both ports open, to directly enter thestream of purified blood emanating from the dialyzer and flowing back tothe patient.

It should be noted by persons of ordinary skill in the art that thebackup two-way valve 6946 is a redundant safety valve to ensure that, inhemodialysis mode, failure of one valve 6945 does not result in infusionof regenerated dialysate directly into the patient. That is, both valves6945 and 6946 are capable of being actuated by the system to allow fluidto be directed to the patient's venous blood line as a safetyconsideration. In some cases, the two-way back-up valve 6946 can be asingle valve to allow or stop fluid flow.

It should be further noted by persons of ordinary skill in the art thatvalves as described in the description above are termed as “bypass” or“two-way” depending upon their use. Thus, valves are termed “bypassvalves” when they bypass a component, such as the dialyzer. Otherwisethey are termed “two-way valves” and simply direct the flow in at leasttwo directions. The bypass and two-way valves can, however, be identicalin construction.

The two-way valves can be fabricated as elastomeric membranes that arepressed against an orifice by a mechanism contained inside the dialysismachine to stop flow from having fluid contact with the rest of thefluidic circuit, as further discussed below.

Two-way valves 6945 and 6946 can be used for changing the mode ofoperation of the blood processing system. Referring to FIG. 6C, fluidflow in blood and dialysate circuits 6920 and 6925 is depicted. With thesystem operating in a hemofiltration mode or in a single-passhemodiafiltration mode, spent dialysate tube 6903 is connected to adrain while fresh dialysate tube 6904 is connected to fresh, ultrapure,and injectable-grade dialysate in reservoirs 6952. Fresh dialysate fromreservoirs 6952 passes through a ball-valve drip chamber 6953 and thenpasses through a heater bag 6954 to flow into fresh dialysate tube 6904.The rest of the elements and fluidic paths of the blood and dialysatecircuits 6920, 6925 are similar to those of FIG. 6B, except that, inhemofiltration, fresh dialysate or replacement fluid is introduced intodialysate circuit 6925 as the spent dialysate is drained and not reused.

As shown in FIGS. 6B and 6C blood circuit 6920 can comprise aperistaltic blood pump 6921 that draws a patient's arterial impure bloodalong tube 6901 and pumps the blood through dialyzer 6905. An optionalpump 6907 injects an anticoagulant, such as heparin, into the drawnimpure blood stream or anticoagulant can be injected as a bolus into thepatient at the start of a treatment. Pressure sensor 6908 is placed atthe inlet of blood pump 6921 while pressure sensors 6909 and 6911 areplaced upstream and downstream of dialyzer 6905. Purified blood fromdialyzer 6905 is pumped through tube 6902 past a blood temperaturesensor 6912, air eliminator 6913, and air (bubble) sensor 6914, and backto a vein of the patient. A pinch valve 6916 is also placed tocompletely stop blood flow if air is sensed by the bubble sensor 6914 inthe line upstream of the pinch valve 6916, thereby preventing the airfrom reaching the patient.

The dialysate circuit 6925 comprises two dual-channel dialysate pumps6926, 6927. Dialysate pumps 6926, 6927 draw spent dialysate solutionfrom the dialyzer 6905 and fresh dialysate from reservoir 6934 (FIG. 6B)or reservoirs 6952 (FIG. 6C). Spent dialysate from the outlet ofdialyzer 6905 is drawn through blood leak sensor 6928 and bypass valve6929 to reach two-way valve 6930. Pressure sensor 6931 is placed betweenvalves 6929 and 6930. An ultrafiltrate pump 6932 is operatedperiodically to draw ultrafiltrate waste from the spent dialysate and tostore the ultrafiltrate waste in an ultrafiltrate bag 6933 (that isemptied periodically). Fresh dialysate from reservoirs 6952 (FIG. 6C)passes through flow restrictor 6935 and pressure sensor 6936 to reachtwo-way valve 6937.

Heater bag 6954 can provide a heating function to raise the temperatureof the fresh dialysate sufficiently so that the temperature of theultrafiltered blood going back to the patient from dialyzer 6905, or theoverall temperature of the mixture of ultrafiltered blood from dialyzer6905 and the fresh dialysate infused directly into the purified blood byactuating the valves 6945, 6946, is equivalent to the body temperatureof the patient, thereby preventing any thermal shock.

FIG. 6D is a schematic diagram showing a dialysate circuit that can beconnected to, combined with, used in conjunction with, or used in placeof a dialysate circuit for, an extracorporeal blood treatment machine302, for example, the NxStage System One blood treatment machineavailable from NxStage Medical, Inc., of Lawrence, Mass. An incomingdialysate line 312, connected to a three-way valve 314, brings fresh orregenerated dialysate into blood treatment machine 302 where the freshor regenerated dialysate can be used to treat blood flowing through anextracorporeal blood circuit. The fresh or regenerated dialysate can bedirected through, for example, a dialyzer, through which also flowsblood to be treated. A pressure sensor 306 is provided to monitor thepressure of the incoming dialysate in line 312. Subsequent to ionexchange contact with blood in blood treatment machine 302, used orspent dialysate can exit blood treatment machine 302 through a dialysatereturn line 308. A pressure sensor 304 can be operatively arranged tosense the pressure of used dialysate flowing through return line 308.Pressure sensor 304 can also act as a through-conduit in fluidcommunication with a pump control loop 328 leading to a first dialysatepump 324. Instead, or in addition, used dialysate exiting bloodtreatment machine 302 can pass through return line 308 and be directed,through a three-way valve 310, into a return conduit 316, throughanother three-way valve 320, and continue to dialysate pump 324. Alongreturn conduit 316, a potassium sensor 380 can be disposed to sense theconcentration of potassium in the used dialysate.

Three-way valve 310 and three-way valve 314 can be controlled by acontroller or control unit (not shown) to shut-off dialysate conduit 312and shut-off return line 308 to provide a bypass pathway that avoidsblood treatment machine 302. The bypass pathway can be used, forexample, in priming the dialysate circuit, further purifying thedialysate, or both. Three-way valve 320 can be controlled by the controlunit to enable priming solution to be drawn by dialysate pump 324, froma prime tank 318 that can hold, for example, eight liters of a primingsolution. The priming solution can thus be drawn into the dialysatecircuit. A temperature sensor 322 can be provided to sense thetemperature of the used dialysate or priming solution entering dialysatepump 324.

Dialysate pump 324 is configured to pump used dialysate or primingsolution through a sorbent cartridge 332 for the purpose of regeneratingused dialysate or purifying the priming solution. A pressure sensor 326can be provided, in fluid communication with a fluid conduit 327connecting dialysate pump 324 to sorbent cartridge 332, that can providea bypass circuit for the purpose of limiting or controlling the flow ofdialysate into and through sorbent cartridge 332, especially underexceedingly high-pressure conditions. Dialysate or priming solution thatdoes pass through sorbent cartridge 332 is then directed through anammonia (NH4+) sensor 334 before the sorbent cartridge-treated dialysateor priming solution flows through a reservoir conduit 336 and into areservoir 338. Reservoir 338 can be in the form of a twelve-literreservoir, in the form of two six-liter reservoirs, or the like.Regenerated dialysate, or purified priming solution, is pulled fromreservoir 338, by a second dialysate pump 360 from which the fluid ispushed through a conditioning and temperature controller 368, through aheater 370, through a three-way valve 366, through a second potassiumsensor 390, through a conditioning and temperature control and safetysystem 374, and to three-way valve 314. From three-way valve 314, theregenerated dialysate or priming solution can be directed through inputconduit 312 and into blood treatment machine 302. Through the use ofthree-way valve 366 and other three-way valves 364, 346, and 356, theregenerated dialysate or priming solution can be further conditioned,including, for example, with supplemental potassium, before beingdirected through three-way valve 366 and toward three-way valve 314.Potassium sensor 390 can instead be incorporated into conditioning andtemperature controller 368 and/or conditioning and temperature controland safety system 374.

Although fresh dialysate, regenerated dialysate, or priming solution canfill or partially fill the dialysate circuit, including reservoir 338,further operation of the circuit will hereafter be exemplified withreference to regenerated dialysate, for the sake of simplicity.Regenerated dialysate pushed from second dialysate pump 360 towardthree-way valve 366 exerts pressure that can be sensed by a pressuresensor 362. Under conditions of exceedingly high pressure, pressuresensor 362 can act as a ball valve or similar device to enable a flow ofregenerated dialysate therethrough and into a pump control loop 361 thatleads back to second dialysate pump 360. The temperature of theregenerated dialysate pushed by second dialysate pump 360 can bemeasured or sensed by a second temperature sensor 372. A control signalsent from second temperature sensor 372 to the control unit can be usedby the control unit to operate heater 370 to provide more or lessheating of the regenerated dialysate depending upon the temperaturesensed.

The temperature, the electrolytes concentrations, the pH, and otherproperties of the regenerated dialysate can be sensed by conditioningand temperature controller 368 and corresponding signals can be sent tocontrol electronics, for example, the control unit. Based on the signalsprovided, the control unit can send control signals to a conditioningcontrol pump 358 and a three-way valve 356 to control the infusion of abicarbonate solution into the regenerated dialysate flowing throughconduit 340. The bicarbonate solution can be generated, as needed, bycontrolling the supply of a concentrated bicarbonate solution from aone-liter reservoir 352, and dilution water from a four-liter reservoir354, by control of three-way valve 356 and conditioning control pump358. A pump control loop 359 is provided to return conditionedregenerated dialysate to conditioning control pump 358, depending uponthe parameters sensed by conditioning and temperature control unit 368.

In addition to conditioning the regenerated dialysate with a bicarbonatesolution, the regenerated dialysate can also be conditioned with a saltand dextrose solution, an electrolyte solution, and a potassiumsolution. A pump 348, herein referred to as electrolytes pump 348, canpull the various solutions through a four-way valve 346 and pump theresultant mixture of solutions into conduit 340 toward second dialysatepump 360. A pump-to-pump control loop 363 provides a fluid communicationfrom pump 360 to pump 348 for the purpose of recirculating dialysateflow to pump 348, equalizing the fluid flow resulting from both pumps360 and 348, and relieve overpressure.

Four-way valve 346 is in fluid communication with a 150 mL reservoir 342containing a salt and dextrose solution, a 500 mL reservoir 344containing an electrolytes solution, and a 100 mL reservoir 345containing a supplemental potassium solution. Based on signals receivedfrom conditioning and temperature control unit 368, conditioning andtemperature control and safety system 374, and at least one of potassiumsensors 380 and 390, the control unit can send control signals tofour-way valve 346 to control the mixing of the solutions fromreservoirs 342, 344, and 345, and thus control the combined mixture ofsolutions entering electrolytes pump 348.

Yet another three-way valve 364 is provided that can be used inconjunction with a three-way valve 366 to recirculate dialysate forfurther conditioning with additional bicarbonate solution pulled throughthree-way valve 356, with additional electrolytes, salt, and sugarsolutions pulled through four-way valve 346, or with both. Theconcentration of potassium in the regenerated dialysate, measured bypotassium 390, can be controlled by controlling four-way valve 346 toenable more or less supplemental potassium to be pulled from reservoir345 into the dialysate circuit. A target concentration of potassium inthe regenerated dialysate can be based on the concentration of potassiumsensed, in the used dialysate, by potassium sensor 380. Sensed potassiumconcentration from both potassium sensors 380 and 390 can be sent to thecontrol unit and used by the control unit to regulate the infusion ofsupplemental potassium solution from reservoir 345.

The specific components that can be used for the various elements shownin FIG. 6D can include suitable components that are well-known to thoseof skill in the art. Many suitable components that can be implementedare described and shown in U.S. Patent Application Publication No. US2011/0315611 A1 to Fulkerson et al., which is incorporated herein in itsentirety by reference. Many of the components can be arranged in acartridge or manifold, as described in US 2011/0315611 A1, and cansimilarly be arranged in a cartridge or manifold according to thepresent teachings. Pump 324 can be used as a cartridge-in pump undersuch circumstances.

Each of pumps 324, 360, 358, and 348 can independently be anon-occluding pump, an impeller pump, a centrifugal pump, an occludingpump, a peristaltic pump, or the like. Each of pumps 324 and 360 canindependently provide a flow rate of from 50 mL/min to 500 mL/min, canprovide a maximum pressure of 50 psig, and can provide accuracy thatdeviates by no more than 1 or 2 percent. Pump 358 can provide a flowrate of from 1 mL/min to 50 mL/min. Pump 348 can provide a flow rate offrom 0.5 mL/min to 50 mL/min, and an accuracy that deviates by no morethan 1 or 2 percent.

Temperature sensor 322 can comprise an infra-red temperature indicator.Exemplary indicators that can be used include the Omega, Smart-micro IRt/c temperature indicator no. OS35RS-100C-V5-12V that can indicate amaximum temperature of 100° C., provide an output of from 0 to 5 volts,and can run on 12-volt DC. Omega temperature indicators are availablefrom OMEGA Engineering, Inc. of Norwalk, Conn. Temperature sensor 372can comprise of the same type or same model of temperature indicator assensor 322.

Heater 370 can comprise any suitable heating assembly known to those ofskill in the art. The heater can be an in-line flow-through heater.Heater 370 can comprise any suitable heating assembly known to those ofskill in the art. The heater can comprise an in-line flow-throughheater. Heater 370 can be configured, for example, to provide adialysate temperature change of up to 50° C. in dialysate flowing at aflow rate of up to 500 mL/min.

Conditioning and temperature controller 368 can include one or moreindicators, provide an output voltage of from 0 to 10 volts, provide apre-treatment range of from 5 to 15 mS/cm in the temperature range offrom 5° C. to 50° C., and provide a treatment range of from 12 to 14.5mS/cm in the temperature range of from 35° C. to 42° C. Conditioning andtemperature control and safety system 374 can include an indicator,provide an output voltage of from 0 to 10 volts, and provide a treatmentrange of from 13 to 14 mS/cm in a temperature range of from 35° C. to42° C.

Each of valves 310, 314, and 320 can independently be a three-way ortriple-port valve having a maximum allowable working pressure of 50psig. Each of valves 356, 364, and 366 can be a three-way or triple-portvalve having a maximum allowable working pressure of 30 psig. Valve 346is a four-way valve having a maximum allowable working pressure of 30psig. Other suitable valves and pressure ratings can be used. Each valvecan independently be an electromagnetically actuated valve, a solenoidvalve, a plunger valve, or the like. Custom-made valves from CustomValve Repair of New Castle, Pa. can be used. Valves available fromQosina of Ronkonkoma, N.Y., can be used. Many of the valves describedand shown in U.S. Patent Application Publication No. US 2011/0315611 A1can be used.

Each of pressure sensors 326 and 362 can independently comprise apressure transducer having a pressure sensing range of from 0 to 30 psi,a pressure over-range protection value of 60 psi, an operating temperaterange of from −28° C. to 54° C., and a compensated temperature range offrom −1° C. to 54° C. Other suitable ranges and values can be used.Exemplary pressure transducers exhibiting such parameters include theHoneywell pressure transducer 1865-07G-KDN available from Honeywell,Morristown, N.J.

Each of pressure sensors 304 and 306 can independently have a pressuresensing range of from 0 to 15 psig, a pressure over-range protectionvalue of 45 psig, an operating temperature range of from −28° C. to 54°C., a compensating temperature range of from −1° C. to 54° C., and anaccuracy that deviates by no more than 2.5 percent. An exemplarypressure sensor exhibiting such parameters is the Honeywell pressuretransducer 1865-03G-KDN, available from Honeywell, Morristown, N.J.Other suitable pressure transducers can be used.

FIGS. 7A and 7B are a cross-sectional side view and top view,respectively, of a flow cell 700 for sensing blood potassiumconcentration in an extracorporeal blood circuit, according to one ormore embodiments of the present invention. Flow cell 700 comprises abody 702, a lid 704, a pair of electrodes comprising a sensing electrode706 and a reference electrode 708, and a wire harness 710. Blood flowingthrough an extracorporeal blood tubing 712 enters the interior 714 offlow cell 700 through an inlet 716 and exits flow cell 700 through anoutlet 718. Electrical leads from the electrodes are harnessed by wireharnesses 710 and are in electrical communication with ion selectiveelectrode circuitry (not shown) as described herein. Signals from theelectrodes are used to sense the blood potassium concentration in theblood flowing through the flow cell. The electrodes can comprisepotassium permeable ion selective membranes.

Lid 704 can comprise catches 720 that engage with protrusions 722 onbody 702 to lock lid 704 to body 702. Two release tabs 724 are providedto release lid 704 from body 702. Lid 704, including electrodes 706 and708, can be sterilized and reused whereas flow cell body 702 can be madeas a disposable component and can be protected by a temporary cover lidto keep interior 714 of flow cell 702 sterile until use. During use,electrodes 706 and 708 are connected to lid 704 and are aligned withthrough-holes in a top 726 of body 702. O-rings 728 and 730 are providedto seal top 726 of flow cell body while electrodes 706 and 708 protrudeinto interior 714 of flow cell 700. By being positioned in interior 714,electrodes 706 and 708 can be used to sense blood potassiumconcentration in blood flowing through flow cell 700. Electrical leads746 and 748 electrically connect sensing electrode 706 and referenceelectrode 708, through wire harness 710, to ion selective electrodecircuitry that can be fully encompassed by, a part of, or independentfrom the control and computing unit of the dialysis system. A controland computing unit is provided that as a data processing unit, forexample, a microprocessor, on which a data processing program, forexample, software, can run.

FIG. 8 shows another embodiment of the present invention, wherein ahemodialysis device is provided that has a blood treatment unit in theform of a dialyzer or filter 801 that is divided into a blood chamber803 and a dialysate chamber 804 by a semipermeable membrane 802. Anarterial tube 806 is connected by means of an arterial puncture cannula805 as a patient connection to a patient's fistula or shunt (not shown)and leads to an inlet to the blood chamber 803 of dialyzer 801. A venoustube 807 that is connected by means of a venous puncture cannula 808, asa patient connection to the patient's fistula or shunt, goes out fromthe outlet of the blood chamber 803 in dialyzer 801. A blood pump 809 isconnected to arterial tube 806 and pumps blood in the extracorporealblood flow circuit I. Blood pump 809 is preferably an occlusion pump,for example, a peristaltic pump. The arterial and venous tubes form thearterial and venous branches 806, 807, respectively, of theextracorporeal blood flow.

The dialysate flow circuit II through the dialyzer includes a dialysatesource 810 to which a dialysate supply line 811 is connected that leadsto the inlet for dialysate chamber 804 of dialyzer 801. A dialysateoutlet line 812 leads from the outlet of dialysate chamber 804 of thedialyzer 801 to an outlet 813, for example, a drain or storage bag. Adialysate pump (not shown) is connected to dialysate outlet line 812.

The dialysis device is controlled by a central control and computingunit 814 that has a computer, microprocessor, or other processor that isprogrammed such that the steps required for controlling the individualcomponents and for detecting and evaluating measured values areperformed. In the present exemplary embodiment, a control and computingunit 815, in the form of a computer making up or being a part of amonitoring device, is a component of central control and computing unit814. Either or both of central control and computing unit 814 andcontrol and computing unit 815 can have a data processing unit, forexample, a microprocessor, on which a data processing program (software)can run.

An arterial potassium sensor 818A is provided on arterial tube 806downstream of the arterial cannula 805 and upstream of blood pump 809,and a venous potassium sensor 818B is provided on venous tube 807upstream of venous cannula 808. The potassium sensors 818A and 818B, mayeach individually be any one of the potassium sensors disclosed and/orshown herein. An arterial cut-off unit 816, such as a valve, is providedon arterial tube 806 downstream of arterial cannula 805 and upstream ofblood pump 809, and a venous cut-off unit 817 is provided on venous tube807 upstream of venous cannula 808. The cut-off units 816 and 817, maybe electromagnetically actuatable tube clamps. In principle, however,the arterial cut-off unit 816 may omitted.

The monitoring device can have, as shown, an alarm unit 819 that, in thepresent exemplary embodiment, is a component of the alarm unit for theblood treatment device. Potassium infusion rates, low potassium levels,or high potassium levels, can be trigger alarms and can indicate a needfor action. Alarm unit 819 has a first signal generator 819A and asecond signal generator 819B. The first signal generator 819A providesonly a preliminary alarm, for instance only a visual signal, anindication on the screen of the machine, or a corresponding recording,while the second signal generator 819B provides an acoustic and/orvisual and/or tactile alarm that is immediately perceivable.

For controlling the individual components and for detecting the measuredvalues, the blood pump 809 is connected to central control and computingunit 815 via a control line 809′, connected to alarm unit 819 via acontrol line 819′, connected to the arterial and venous cut-off units816 and 817, via control lines 816′ and 817′, and the arterial andvenous potassium sensors 818A and 818B, via control lines 818A′ and818B′. The control and computing unit 815 is programmed such that,during the blood treatment, the arterial and venous serum potassiumconcentrations are measured continuously using signals generated bypotassium sensors 818A and 818B. Pressure sensors (not shown), can alsobe included, for example, to monitor one or more vascular accesses.

Blood serum potassium concentration can be control during a bloodtreatment session by sensing, measuring, and/or calculating serum bloodlevel values using potassium sensors 818A and 818B. As blood serumpotassium concentrations pre-dialyzer, measured in arterial tube 806 arecompared with blood serum potassium concentrations post-dialyzer,measured in venous tube 807, the central control and computing unit 805regulates the infusion of supplemental potassium into the dialysateflowing through dialysate line 811 for exchange with blood in dialyzer801. The central control and computing unit 805 regulates the infusionof supplemental potassium into the dialysate flowing through dialysateline 811 by sending a control signal via a control line 821′ to apotassium supply device 821 comprising a container containing a supplyof potassium ions, for example, a potassium salt solution, and a syringepump driven by a stepper motor and configured to drive or otherwiseforce the supply of potassium ions into the stream of dialysate flowingthrough hose 811 and into dialyzer 801. A one-way valve can be providedto prevent back-flow of dialysate toward potassium supply device 821.The stepper motor and syringe pump are designed to receive controlsignals from the control and computing unit 815 or from another central,or separate, computer or processor, to control the addition ofsupplemental potassium into the dialysate, based on signals receivedfrom potassium sensors 818A and 818B.

If a fault is suggested and an alarm signal is generated, the controland computing unit 815 generates a control signal for the arterial andvenous cut-off units 816 and 817 so that the cut-off units can beclosed. Thus, the arterial and venous lines 806 and 807 can becompletely closed-off from the patient in the event of a potassiumlevel-related emergency or warning. The control and computing unit 815can further generate a control signal for alarm unit 819 so that secondsignal generator 819B can provide a preferably acoustic alarm. After theacoustic alarm, medical staff can take the required measures.

During verification of a potassium level-related fault, the control andcomputing unit 815 continuously monitors whether a certain time intervalthat is prespecified by a timing unit element, has elapsed. Once thetime interval has elapsed, the arterial and venous tube clamps 816 and817 are automatically closed for safety reasons. This ensures that it isonly possible to verify the fault and continue the blood treatmentwithin narrow temporal limits.

According to various embodiments, a potassium sensor 818C can instead,or additionally, be used, as a sensor for providing signals to beevaluated and/or considered by control and computing unit 815 in theregulation of potassium supply device 821. The level or concentration ofpotassium in spent dialysate, or ultrafiltrate, passing through useddialysate tube 812, can be sensed, measured, and/or calculated toprovide or be used in providing a control signal to regulate operationof potassium supply device 821. The control signal sent from potassiumsensor 818C to regulate operation of potassium supply device 821 can betransmitted along control line 818C′, or wirelessly, to control andcomputing unit 815 and/or to central control and computing unit 814,wherein the control signal can be processed and used to regulate theinfusion of supplemental potassium from potassium supply device 821 tofresh dialysate hose 811.

FIG. 9 shows, in a very simplified schematic representation, anapparatus for peritoneal dialysis, in which a hose set 901 includes abranch line 909 that can be permanently attached to, or dis-connectablefrom, a supplemental potassium supply device 910 comprising a containercontaining a supply of potassium ions, for example, a potassium saltsolution, and a syringe pump driven by a stepper motor and configured todrive or otherwise force the supply of potassium ions into the stream ofperitoneal dialysis solution flowing through hose 920 and into theperitoneal cavity of a patient 940. The stepper motor and syringe pumpare designed to receive control signals from a central or separatecomputer or other processor to control the addition of supplementalpotassium into the peritoneal dialysis solution based on signalsreceived from potassium sensors 907, 927, and 937, which signals areprocessed by the central computer or other processor. The centralcomputer has a data processing unit, for example, a microprocessor, onwhich a data processing program (software) can run.

A peristaltic pump 931 pulls peritoneal dialysis solution from a supplybag 902, and pulls supplemental potassium supplied from supplementalpotassium supply device 910. Peristaltic pump 931 pushes the resultingsolution through hose portion proper 920 from peristaltic pump 931,through potassium sensor 927, and into the peritoneal cavity of patient940.

Hose set 901 has a free end 903 connected to a supply bag 902 and cancomprise a luer fitting, a threaded screw and threaded nut connector, acompression fitting, or another coupler, to connect free end 903 tosupply bag 902. Free end 903 is also connected to, or passes through, afirst potassium sensor 907 that can be provided to sense the potassiumconcentration in the peritoneal dialysis solution. First potassiumsensor 907 can be omitted from use or inclusion, for example, if theconcentration of the potassium supply in bag 902 is known, or for anyother reason. A second potassium sensor 927 can be provided to sense thepotassium concentration in the peritoneal dialysis solution after mixingwith any supplemental supply of potassium but prior to infusion into theperitoneal cavity. The second potassium sensor 92 may also, or instead,be omitted from use or inclusion.

A first lumen 928A of a double-lumen peritoneal catheter 928 is providedfor supplying peritoneal solution into the peritoneal space or forcarrying away the solution from the peritoneal space of the patient.Double-lumen peritoneal catheter 928 also comprises or is connected to asecond lumen 928B, for example, designed as part of peritoneal catheter928. A hose line 929 is permanently or dis-connectably connected tosecond lumen 928B and also to a bag 930 for collecting used or spentperitoneal solution.

As shown in FIG. 9, an electrocardiogram (EKG) signal, sensed by EKGlead 950 on patient 940, can be processed by a central or separatecomputer or other processor to provide an additional or alternativecontrol signal for regulating and/or controlling supplemental potassiumsupply device 910 and the addition, through branch line 909, ofsupplemental potassium into the peritoneal dialysis solution. Asdescribed below with reference to FIGS. 15 and 16, the electrocardiogramsignal sensed and transmitted from EKG lead 950 can be, or include, a Twave, and the T wave can be digitally analyzed or processed toaccurately estimate blood serum potassium in the patient. A wire,control line, or other signal transmitting device or system (not shown)can be attached to and extend from EKG lead 950, or a wireless systemcan be used, to transmit the electrocardiogram signal sensed to thecentral or separate computer or other processor. The central or separatecomputer can have a data processing unit, for example, a microprocessor,on which a data processing program (software) can run.

Sensed potassium concentration signals can be signal-processed, ifdesired or needed, so as to be interpreted and interrogated. Based onincoming and outgoing concentrations of potassium, with respect to thepatient's peritoneal cavity, adjustments can be made, for example, tomaintain a slow, uniformly consistent decrease in potassiumconcentration in the effluent to be collected in bag 930, over a portionof, or the entire, treatment. Rather than a linear uniformly consistentdecrease, curves of desired potassium reductions over a treatment periodcan be followed, and the treatment parameters can be controlled based onsensed, measured, and/or processed potassium concentration signals.Curves of rates of potassium concentration reduction over time, thathave been standardized, made into sets of standards, or otherwise reliedupon can be followed to ensure proven safe treatment methods that reducepotassium serum concentrations safely, efficiently, yet at rates thatreduce or eliminate risks of hypokalemia and shock effects associatedwith sudden and drastic reductions in serum potassium as might beexperienced from overly aggressive and/or fast treatment methods.

FIG. 10 shows the components for operating a blood serum potassiumdetection apparatus in an extracorporeal blood treatment, particularlyin a dialysis device, illustrated in a very simplified schematicdepiction. The extracorporeal blood treatment apparatus includes anexchange unit, for example, a dialyzer or filter 201, that is subdividedinto a blood chamber 203 and a dialysis fluid chamber 204 by asemi-permeable membrane 202. An arterial blood supply line 205 leadsfrom a patient to the blood chamber of dialyzer 201, while a venousblood return line 206 branches off from the blood chamber and leads tothe patient. A blood pump 207 that is disposed in the arterial bloodline 205 pumps the blood through an extracorporeal blood circuit I.

The dialysate fluid system II of the dialysis device is only partiallyshown in the drawing. It comprises a dialysis fluid supply line 208leading to the dialysis fluid chamber 204 and a dialysis fluid dischargeline 209 that branches off from the dialysis fluid chamber 204 of thedialyzer 201.

The arterial and venous blood lines 205, 206 are hose lines that are atleast partially transparent with respect to electromagnetic radiation,particularly light. The blood treatment apparatus includes a centralcontrol unit 210 that controls the individual components, for exampleblood pump 207. The apparatus 211 for determining the blood serumpotassium can be a structural component of the blood treatmentapparatus, such that it can utilize components that are parts of theblood treatment apparatus, for example, the same central control andcomputing unit, computer, or other processor. The central control andcomputing unit can have a data processing unit, for example, amicroprocessor, on which a data processing program (software) can run.

The apparatus 211 for detecting blood serum potassium includes ameasuring unit 212 comprising a unit 213 into which a hose line of theextracorporeal blood circuit can be fitted, particularly, venous bloodline 206. Measuring unit 212 comprises a transmitter and receiver unit214 for coupling radiation in and out.

A data line 215 connects measuring unit 212 to a computing and analyzerunit 216, for example, comprising a central processing unit (CPU)including a memory. The computing and analyzer unit 216 is able toexchange data with a central control unit 210 of the blood treatmentapparatus via a signal line 217. Either or both of computing andanalyzer unit 216 and central control unit 210 can have a dataprocessing unit, for example, a microprocessor, on which a dataprocessing program (software) can run.

FIG. 11A shows a partial view of measuring unit 212, seen as asimplified cut representation. Measuring unit 212 includes a unit 213with a receptacle 213A into which a blood line such as venous blood line206 is clamped. The receptacle 213A includes four flat contact surfacesthat are disposed at right angles relative to each other, and the hoseline rests there against. FIG. 11A depicts only a single transmitter214A and a single receiver 214B of transmitter and receiver unit 214.The radiation that is emitted by transmitter 214A passes through thehose line and into the blood that flows in the hose line 206, whereinthe radiation emerging from the blood traverses through the hose lineand is directed to receiver 214B. Due to the fact that the axes of thetransmitter and receiver 214A, 214B are disposed at a right angle withrespect to one another, the receiver receives the scattered radiation.For the detection of the transmitted radiation, the transmitter and thereceiver 214A, 214C are disposed opposite each other on a shared axis,as depicted in FIG. 11B.

FIG. 11C shows an alternate embodiment of measuring unit 212 that isintended for a blood cartridge 218, wherein the blood flows through ablood channel 219, not through a hose line. Blood channel 219 isconfigured inside the cartridge. The part of the blood cartridge 218forming channel 219 is made of a transparent material, for example,polycarbonate. Measuring unit 212 includes, for example, unit 213 andunit 213 is open on one side such that cartridge 218 can be fastenedtherein or that can otherwise be fastened to the cartridge. Measuringunit 212 and cartridge 218 thus constitute separate units, whereinmeasuring unit 212 is a component of the blood treatment apparatus andcartridge 218 can be exchanged and made disposable.

FIG. 12 shows a representation of the principle that is embodied in ameasuring apparatus with a transmitter and receiver unit 214 comprisinga plurality of transmitters and receivers to be able to determine theblood serum potassium value by a variety of different measuring methods.Blood flows inside a transparent blood hose line such as venous line206, in unit 213, and is clamped in unit 213 of the device fordetermining blood serum potassium (not shown in FIG. 12). Themeasurement apparatus for the transmission measurement includes atransmitter S and a receiver that are disposed on both sides of the hoseline on a shared axis, facing each other. The receiver for the detectionof the transmitted radiation is designated as TS. The axis of thetransmitter S and receiver TS extends at a right angle relative to thelongitudinal axis of hose line 206. Irradiation or light emitted fromtransmitter S, which propagates in the direction of the axis andimpinges on blood flowing inside the hose line, is received by thereceiver TS. The receiver TS supplies a measured signal that isproportionate to the intensity of the light and that is analyzed in thecomputing and analyzer unit 216. Lambert-Beer's law describes therelationship between the intensity of the incoming and emerging light.By selecting an appropriate transmitter and receiver pair, the bloodserum potassium value can be calculated in computing and analyzer unit216. For example, by using an ultra-violet (UV) transmitter and a UVreceiver, an optical system for measuring UV absorbance can be used tomeasure blood serum potassium. By using a near infrared (NIR)transmitter and an NIR receiver, an NIR spectroscopy system formeasuring an NIR spectrum can be used to determine a blood serumpotassium value. By using a laser transmitter and a spectroscopicreceiver, a laser-induced breakdown spectroscopy (LIBS) system can beused to measure blood serum potassium. None of these exemplary systemsrequires direct fluid contact with the blood to determine blood serumpotassium relative values or exact measurements.

For the detection of scattered radiation (scattered light measurement),the measurement apparatus includes three further receivers as shown inFIG. 12. The receiver for the detection of the backward scatter(reflection) is designated as RS, the receiver for detecting the forwardscatter is designated as VS, and the receiver for detecting the lateralscatter is designated as SS. The receivers RS and VS are disposed at thedistance x relative to the transmitter S and receiver TS for thetransmission measurement. The transmitter S and the receiver TS for thetransmission measurement and the receiver RS and VS for the detection ofthe backward scatter and forward scatter are arranged inside a planethrough which the longitudinal axis of the hose line 206 extends. Thereceiver RS for detecting the reverse scatter, the receiver VS fordetecting the forward scatter, and the receiver SS for detecting thelateral scatter are arranged inside a plane that is perpendicularrelative to the former plane. For the detection of the lateral scatter,the spacing x can also be zero.

The wavelength of the radiation that is emitted by the transmitter S,particularly the emerging light, can be in any suitable wavelengthrange. For some detection systems, the radiation is not in the visiblerange of 380 nm to 780 nm. The transmitter can comprise an LED, and OLEDsource, or the like. The transmitter can be a narrow-band LED source,for example, having a peak wavelength that is at 805 nm. The transmittercan comprise a laser source, an incandescent source, a fluorescentsource, a quantum dot source, or the like. The receivers can bephotodiodes, charge-coupled devices, or the like.

The blood serum potassium value can be determined by two differentmeasuring methods. For example, the first measuring method can include areflection measurement and the second measuring method can include atransmission measurement. The computing and analyzer unit 216 cancalculate the difference between the value measured by the reflectionmeasurement and the value measured by the transmission measurement,wherein conclusions as to the amount of potassium in the blood serum aredrawn based on the difference of the two measured values. Conclusionsthat increased amounts of potassium are present can be based on anincrease of this difference. An equation residing in the computing andanalyzer unit 216, that describes the dependent relationship of thedifference of the values and the amount of blood serum potassium, can beused for calculating the amount of potassium as a function of thedifference of the measured values.

The amount of potassium measured, sensed, calculated, or determined canbe represented on a display unit 216B of device 211 for detection. Thedevice can include an alarm unit 216C that outputs an alarm when apreset potassium amount rate is exceeded or not met. When a preset bloodserum potassium amount is exceeded, it is also possible to generate acontrol signal that is received by the central control unit 210 of theblood treatment apparatus via line 217, such that it is possible toengage with the machine control of the blood treatment apparatus.

In a specific UV-absorbance embodiment, only reflection and transmissionmeasurements of UV wavelengths, are used. FIG. 13 shows a firstalternate embodiment of the measurement apparatus for the reflection andtransmission measurements. This embodiment corresponds to the embodimentas shown in FIG. 12, wherein the receivers VS and SS for the forward andlateral scatter have been omitted. Corresponding parts are thereforeidentified by the same reference signs. The measurement apparatus ofFIG. 13 allows both receivers TS and RS to measure reflected and/ortransmitted UV radiation simultaneously.

FIG. 14 shows an alternate embodiment that includes a measurement pathfor the transmission measurement with a transmitter S1 and a receiverTS, RS that is also used for the reflection measurement. A secondtransmitter S2 is provided for the reflection measurement that isdisposed, observing a spacing x of the measurement path, for thetransmission measurement. This measurement apparatus does not allow forsimultaneous but only for alternate measurements using the two measuringmethods. For the transmission measurement, the computing and analyzerunit 16 activates the transmitter S1 for the transmission measurementand deactivates the transmitter S2 for the reflection measurement, whilethe transmitter S1 is deactivated for the reflection measurement and thetransmitter S2 is activated for the reflection measurement. Bothmeasurements can be done immediately in succession.

These exemplary apparatuses according to the present invention allow fora non-invasive, continuous detection of blood serum potassium in wholeblood. The apparatuses are characterized by a simple hardware setup andeasy analysis of the measured results. The apparatuses can be used inany blood treatment apparatus comprising an extracorporeal bloodcircuit. For quality assurance purposes, it is also feasible to use theapparatus for detecting blood serum potassium concentrations in units ofstored blood. To this end, the receiving unit can be configured foraccommodating a unit of stored blood or a hose line on a unit of storedblood.

FIG. 15 shows a typical QRS-T-wave complex from an idealizedelectrocardiogram (ECG) and shows how to define the negative slope andamplitude of the T wave, which can be used to compute the ratio TS/A forestimating extracellular K+ concentration in the patient from whom theECG was obtained. As can be seen from FIG. 16, the inverse of the TS/Aratio, i.e., (TS/A [s−1]), correlates squarely with the concentration ofextracellular K+, as was established in the article of Corsi et al.,Noninvasive quantification of blood potassium concentration from ECG inhemodialysis patients, SCIENTIFIC REPORTS, 7:42492, DOI:10.1038/srep42492 (published Feb. 15, 2017), which is hereinincorporated by reference in its entirety. Thus, by taking ECGmeasurements from a patient, computing a TS/A ratio value or an averagedTS/A ratio value, and comparing the value to a graph, matrix, table, orlook-up table, for example, in a computer memory, the concentration ofextracellular K+ in the patient can be estimated non-invasively, withoutthe need to calibrate or sterilize a potassium sensor. The method alsoaffords a computation of extracellular K+ concentration in the patientwithout the need to irradiate the patient's blood or flow the patient'sblood through a special flow channel, cartridge, or other analysischamber. Moreover, the method provides a safe and easy way to analyzethe concentration of extracellular K+ in the patient before, during, andafter a dialysis treatment. Furthermore, the use of, addition of, and/orinfusion of potassium or supplemental potassium, to a dialysate, can becontrolled based on the concentration of extracellular K+ so calculated.

The comparative data and/or correlating potassium concentrations cancome from data prepared by recording ECGs and comparing the TS/A valuesto actual blood serum potassium values obtained by blood draws from therespective patients at points in time or periods of time correspondingto when the ECGs were recorded. As an example, 12-lead Holter ECGrecordings obtained from an H12+machine (Mortara Instrument, Inc.,Milwaukee, Wis.), can be retrospectively analyzed. The most significanttwo eigenleads, associated with the first two eigenvalues, can be usedto calculate the downslope and the amplitude of the T-wave for eachbeat. An ECG-based potassium estimator (KECG) can be defined as aquadratic function of the median value of TS/A, automatically computedover a 2-minute window at intervals of 15 minutes. ECG data can beexported and analyzed by implementing a dynamic-link library thatinterfaces to post-processing software also available from MortaraInstrument, Inc. as the SuperECG/Spectrum.

Historical data from testing done on the same patient can be used tobuild a database. Population data from testing done on multiple patientscan be used to build a database. From time to time, actual blood-drawtesting can be used to ensure the ECG-based potassium estimator isproviding accurate estimates and to further build a database ofestimates. Blood sampling and analysis in an off-line machine such asthe OPTIC® CCA-TS2 Analyzer (OPTI Medical Systems, Inc., Roswell, Ga.),can be used to check estimates, be combined with ECG records to build adatabase, or both.

FIG. 16 shows a database in the form of a graph of extracellularpotassium (K+) concentration values measured by standard laboratoryanalysis, and their correlation with computed TS/A values obtained fromconcurrently taken ECG records. The graph shows the relationship betweenTS/A and extracellular potassium ([K+], in mM) in a control group(squares) and in a group of congenital long QT type 2 (LQT2) patients(circles). More details about the relationship and graph are provided inthe Corsi et al. article mentioned above, which is incorporated hereinin its entirety by reference. Other methods and systems that can be usedfor non-invasively computing extracellular [K+] values based on ECG dataare described in U.S. Pat. No. 9,561,316 B2 to Gerber et al., U.S. Pat.No. 9,456,755 B2 to Soykan et al., and U.S. Patent ApplicationPublication No. US 2017/0000936 A1 to Soykan et al., each of which isincorporated herein in its entirety by reference.

Many methods and devices for in-line monitoring of the potassium duringhemodialysis, and that can be used according to the present invention,include those described in Sharma et al., On-line monitoring ofelectrolytes in hemodialysis: on the road towards individualizingtreatment, Expert Review of Medical Devices, 13:10, 933-943, DOI:10.1080/17434440.2016.1230494 (2016), which is incorporated herein inits entirety by reference.

Ion-selective electrodes can be used to measure or otherwise sensepotassium concentrations in blood, dialysate, or both, for example,including blood to be treated, treated blood, fresh dialysate, and useddialysate. ISEs can discriminate between ions. An ideal ISE responds toonly one single type of ion in a mixed solution. The ISE can comprise anelectrochemical sensor wherein a potentiometric signal is measured asoutput. A galvanic cell is formed by immersing a pair of electrodes in asolution. The difference in potential of the two electrodes, known aselectromotive force (EMF), is then measured. If the potential of one ofthe electrodes, i.e., a reference electrode, is constant while the otherelectrode, i.e., an indicator electrode, follows the Nernst equation,then the EMF can be measured. Basically, measured EMF of calibratorfluid(s) and sample are translated into the activity of the ionicspecies of the sample by means of the Nernst equation. Once calibratedwith known concentrations of solution, the EMF can then be related tothe analyte concentration of a sample solution, provided the Nernstequation is met. ISEs can be classified based on the type of membranematerial as glass, crystalline, or polymeric. ISEs can be used inclinical off-line analysis, or in-line using a flow cell, to measureelectrolytes in samples of whole blood, plasma, fresh dialysate, andused dialysate. Potassium concentrations can be measured usingmultichannel analyzers by indirect ISE potentiometry. Exemplary ISEdevices and methods, and flow channels and cassettes that can be usedtherewith, are described in U.S. Pat. Nos. 4,995,959 to Metzner and U.S.Pat. No. 6,752,172 B2 to Lauer, each of which is incorporated herein inits entirety by reference. An ISE can use a passive polymeric membranecomprising ionophores, which determines the ion-selectivity and thusforms a significant part of the electrode. ISEs can be integrated in thein-line monitoring of electrolytes during dialysis. The standardelectrode potential of an ISE changes over time, thus it can befrequently recalibrated.

Devices and methods based on optical measurements can be used to measureor otherwise sense potassium concentrations in blood, dialysate, orboth, for example, including blood to be treated, treated blood, freshdialysate, and used dialysate. Optical sensors offer potential benefitsincluding an inherent immunity to electromagnetic interference,intrinsically contactless through-window interaction, and no damage tothe host system. This offers improved biocompatibility and lessvulnerability to fouling, the absence of electrical currents, and thepotential of simultaneous measurements of multiple substances. The basiccomponents that can be used for optical measurement are alight/illuminating/irradiating source, the fluid (stream) to bemeasured, an optical spectral sorting element a detector for opticalreadout, and a signal processor. The light/illumination or irradiatingsource can be a light-emitting diode (LED), an organic LED, a laser, aquantum dot, an incandescent source, a fluorescent source, or the like.The optical spectral sorting element can be a filter, a set of filters,a diffraction grating, a prism, or the like. The detector for opticalreadout can be a photodiode, a photomultiplier tube, a charge-coupleddevice, or the like. The signal processor can comprise a computer, aCPU, a microprocessor, or the like. Optical sensors, namely, ultraviolet(UV) absorbance and near-infrared (NIR) spectroscopy systems and methodscan be used to estimate potassium concentrations in fresh and spentdialysate and can be used to improve the dialysate dosing andprescriptions. A UV absorbance method can utilize a UV-light source(190-400 nm), a UV-transparent sample holder (cuvette), and aphotodetector. As an example, UV-transmittance can be used forcontinuously monitoring the removal of potassium. Dialysate can bemonitored during HD using UV-absorbance, for example, for monitoring theamount of potassium in spent dialysate. Measurements on collecteddialysate samples can be compared with on-line measurements. Aspectrophotometer can be connected to the fluid outlet of the dialysismachine and the spent dialysate can be made to pass through a cuvette.UV-absorbance can be used to calculate the dialysis dose.

NIR (750-2500 nm) spectrometry can be used for on-line monitoring ofpotassium during dialysis. A temperature-controlled acousto-opticalfilter-based spectrometer can be used to measure potassium concentrationin used or spent dialysate, blood, or treated blood. NIR spectroscopyuses interference and diffraction.

Flame photometry can be used to measure or otherwise sense potassiumconcentrations in blood, dialysate, or both, for example, includingblood to be treated, treated blood, fresh dialysate, and used dialysate.Flame photometry is an atomic emission spectroscopy technique used todetermine the concentration of certain metal ions. The solution isnebulized and injected into a nonluminous gas flame resulting inemission of a characteristic flame coloring. The spectral emission‘fingerprint’ of the flame identifies the element while the intensityindicates the concentration of the elements. This technique is wellestablished and widely used in clinical laboratories for electrolyteconcentration measurement.

Fluorescent photo-induced electron transfer sensors can be used tomeasure or otherwise sense potassium concentrations in blood, dialysate,or both, for example, including blood to be treated, treated blood,fresh dialysate, and used dialysate. The sensor molecules for potassium(K+), based on a fluorescent photo-induced electron transfer (PET)process, can be designed based on a ‘fluorophore-spacer-receptor’ formatas depicted in FIGS. 17A and 17B. In the absence of an analyte, forexample, a cationic species, an electron gets transferred from thereceptor to the fluorophore which results in quenching the fluorescenceprocess. This is called an ‘OFF’ state of the sensor. If an analyte ispresent, then there will be emission of fluorescence signal from thefluorophore. This is called an ‘ON’ state of the sensor. Fluorescenceintensity gives the specific analyte concentration. The choice offluorophore can be entirely based on excitation and emissionwavelengths, whereas the receptor can be chosen based on the analyte tobe determined. Therefore, cheap and stable visible spectrum (400-700 nm)light sources like LEDs or small lasers can be used for excitation. PETsensors can be used to analyze samples of whole blood in a staticmedium. The PET molecules can be fixed on a substrate that acts like acassette. After injecting the sample into this cassette, it is insertedinto an optical readout device. An electrolyte analyzer can utilize anLED source as an excitation source, and photodiodes can be used tocollect the fluorescence emission. The PET sensor molecule can be coatedon a micro-structured optical fiber tip.

Laser-induced breakdown spectroscopy can be used to measure or otherwisesense potassium concentrations in blood, dialysate, or both, forexample, including blood to be treated, treated blood, fresh dialysate,and used dialysate. The elemental analysis in LIBS is very similar toflame photometry, but instead of a gas flame, it uses a strongly focusedlaser pulse to produce a minuscule (typically 2-3-μm diameter) plasmadischarge (the ‘breakdown’) directly in the fluid stream. No nebulizeris needed. Due to the high plasma temperature, neighboring atoms areexcited, and, when falling back to their ground state, send out lightwith a characteristic spectral line pattern. Just as in flamephotometry, the elemental composition can then be determined byresolving the spectrum of the resulting emission spectrum. Theatom-specific spectral peak amplitudes indicate specific ionconcentration. LIBS thus is a truly ‘through-the-window’ measurementtechnology that does not require any direct contact with the fluid. Theabsence of an ion-selective membrane circumvents drift problems frommembrane fouling issues or other Nernst equation disturbances.

FIG. 18 illustrates the principle of LIBS and its implementation of ionmeasurement in spent dialysate. In FIG. 18, the principle of laserinduced breakdown spectroscopy (LIBS) is shown whereby a tiny volumeinside the dialysate stream is temporarily atomized by a focusedhigh-energy pulsed laser. Light emitted from this high-temperature sparkis collected and dispersed, and the atoms present in the specimen can beidentified by specific peaks in the atomic emission spectrum. Theadvantages of LIBS include real-time analysis of elements, no samplepreparation, and high sensitivity, for example, down to a ppm level if ahigh enough laser power is used. The application of LIBS technology canbe used for the on-line determination of potassium and otherelectrolytes within flowing dialysate.

Microsystem technologies can be used to measure or otherwise sensepotassium concentrations in blood, dialysate, or both, for example,including blood to be treated, treated blood, fresh dialysate, and useddialysate. Microsystem technologies can be used for electrolytemonitoring. High-precision devices can be manufactured in a verycost-effective way. Soft lithography using polymeric materials forlab-on-a-chip microfluidic devices provide a platform for point-of-care(POC)-based devices. There are inherent advantages of microsystemtechnologies, namely, (1) smaller sizes ranging from micrometers tonanometers, (2) fast response time due to the small samples sizes, (3)high precision, (4) cost-effectiveness, and (5) ease of integration. Thedetection system can be based either on electrochemical (conductivity,potentiometric), electrical (impedance), or optical (absorbance,reflectance, fluorescence).

One of the most sensitive sensing techniques is based on molecularfluorescence with advantages in terms of specificity, sensitivity, anddetection. Microfluidic systems based on electro-osmotic flow orelectrophoretic separation can be used that employ ion concentrationmeasurement using conductivity detection. This detection scheme iscapable of simultaneously analyzing multiple ions in both contact andcontactless modes. A portable critical care analyzer system calledi-STAT, based on ion-selective potentiometric sensing, can be used. Thesystem consists of a hand-held analyzer and a disposable cartridge. Thecartridge contains a series of ion-sensitive electrodes over which theanalysis fluid passes. Such a system can be used as a POC system toanalyze whole blood. The i-STAT system can be used in an HD unit toanalyze potassium. The i-STAT system can also be used to analyzepotassium in dialysate fluid.

Microfluidic systems and devices comprising polydimethylsiloxane(PDMS)-fabricated micropumps and microchannels can be used with ISEspatterned on a glass substrate to analyze potassium. Such devicesexhibit good sensitivity and reproducibility. The optical sensingschemes in microfluidic devices can be classified as ‘off-chip’ and‘on-chip,’ respectively. The off-chip approach can use the exteriorcoupling of optical components into the device, whereas the on-chipapproach can apply optical functionalities that are integrated into thedevice. The optical components used in such sensing systems can compriseLEDs or lasers as a light source, optical fibers or integratedwaveguides for light guiding, lenses and filters for spectralseparation, and a photodiode or charged-coupled device for detection.The basic optical components of such a system are shown in FIG. 19.

FIG. 19 shows a microfluidic chip 1900, that includes an interrogationzone 1902. A syringe pump 1904 pumps a sample, for example, of blood orused dialysate, through a fluid inlet 1906, and into and through amicrofluidic channel 1908 that passes through interrogation zone 1902.The end of microfluidic channel 1908 is in fluid communication with afluid outlet 1910 in the form of a conduit through which theinterrogated sample can pass to a waste canister 1912.

A light source 1914 generates excitation radiation of one or morewavelengths selected to excite fluorophores in the sample. Theexcitation radiation is directed to interrogation zone 1902 through anoptical fiber 1916. Fluorescence emissions resulting from excitation ofthe fluorophores is gathered or collected by an optical fiber 1918, andappropriate optics if needed, and transmitted through optical fiber 1918to a fluorescence detector 1920 where the fluorescence can bespectroscopically separated, quantitated, and analyzed. Optical sensingcan be implemented either by measuring the direct change in lightintensity, for example, absorbance, or fluorescence, chemiluminescence,a change in the wavelength, or a phase of polarization of light.Spectroscopic detection can be used. The advantages include highsensitivity and low background noise. In order to couple the externalmacroscopic elements into microscopic detection areas, fiber-couplinggrooves can be fabricated in a single-step fabrication process for theintegration of optical fibers. Optical fibers and a fabricated ball lenscan be used for light coupling in taking absorbance measurements.Sensors can be reused and regenerated after rinsing with HCl solution. Adevice can be fabricated in a PDMS and glass substrate for fluorometricdetermination of potassium ions (K+) based on a fluorescent molecularsensor calix-bodipy. The device can comprise a Y-shaped microchannelmolded in PDMS and fixed on a glass substrate, and optical fibers can beused for excitation and fluorescence light collection. Flow injectionanalysis of aqueous solutions of potassium ions can be carried out witha detection limit of 0.5 mM.

MEMS technologies can be used and have enabled the integration ofmechanical and electrical components along with a fluidic part. ManyMEMS-fabricated passive optical components like mirrors, lenses, andfilters can be used and can provide miniaturized light sources andoptical detectors. The integration of waveguides and lenses can improvethe optical path length for absorbance measurement or light focusing forfluorescence measurement. A capillary-assembled microchip can be usedfor sensing potassium. A multifunctional microchip can be used thatcomprises a microchannel network fabricated in PDMS embedded withchemically functionalized square capillaries. The network and outerdiameter of capillaries can have the same diameter. The ion sensingsquare capillaries can be prepared by attaching ion-selective optodemembranes to the inner walls of the capillaries. The device can analyzepotassium with a working range of from 10-5 to 10-1 M.

The present invention includes the followingaspects/embodiments/features in any order and/or in any combination:

1. A dialysis system comprising:

-   -   a dialysis machine configured to perform a dialysis treatment on        a patient;    -   a potassium sensing device configured to sense the concentration        of potassium in at least one of (a) the patient's blood serum,        and (b) spent dialysate resulting from treating the patient with        the dialysis machine, the potassium sensing device further being        configured to generate a sensed value of the concentration of        blood serum potassium;    -   a control and computing unit comprising a processor and a        memory, the processor being configured to receive the value,        compare the value with one or more values stored in the memory,        and to generate a control signal based on the comparison; and    -   a potassium infusion circuit configured to infuse potassium        solution into treatment dialysate, replacement fluid, or both,        that is to be used by the dialysis machine, wherein    -   the control and computing unit is in data transfer communication        with the potassium infusion circuit, and the potassium infusion        circuit is configured to receive the control signal and infuse        potassium solution into the treatment dialysate, replacement        fluid, or both, based on the control signal.

2. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the control and computing unit isfurther configured to store the sensed value of potassium in the memory.

3. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the memory has stored thereinpatient-historical data pertaining to sensed blood serum potassiumconcentration values of the patient obtained under different patientparameters.

4. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the different patient parametersinclude at least one parameter based on the length of time since a lastdialysis treatment was carried out on the patient.

5. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the control and computing unitfurther comprises an input device configured for inputting patientinformation including a time-since-last-treatment value, and the controland computing unit is configured to generate a control signal based onthe input patient parameters and the patient-historical data stored inthe memory.

6. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the memory has stored thereinpopulation data pertaining to sensed blood serum potassium concentrationvalues of a population of different patients obtained under differentpatient parameters.

7. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the control and computing unitfurther comprises an input device configured for inputting patientinformation including a time-since-last-treatment value, and the controland computing unit is configured to generate a control signal based onthe input patient parameters and the population data stored in thememory.

8. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the potassium infusion circuit isconfigured to supply a concentrated solution of a potassium salt at afirst rate and for a first period of time.

9. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the dialysis machine comprises adialysate circuit, the dialysate circuit is configured to use a volumeof dialysate, a time value for the first period of time is stored in thememory in a look-up table, and the time value is categorized in thelook-up table based on the volume of dialysate.

10. The dialysis system of any preceding or followingembodiment/feature/aspect, further comprising an amount of dialysateequal to the volume of dialysate, in the dialysate circuit.

11. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the dialysis machine comprises adialysate circuit including a sorbent cartridge and the treatmentdialysate comprises regenerated dialysate.

12. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the potassium sensing devicecomprises an ion selective electrode pair and is configured to calculatethe concentration of potassium in the patient's blood serum based on ionselective electrode measurements.

13. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the potassium sensing devicecomprises an ultraviolet absorbance detection system that comprises anultraviolet light source and a detector configured to detect ultravioletlight transmitted through the patient's blood serum or the spentdialysate

14. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the potassium sensing devicecomprises a near-infrared spectroscopy detection system that comprises anear-infrared source of radiation, an optical spectral sorting element,and a detector configured to receive spectrally sorted wavelengths fromthe source of radiation and that have passed through the patient's bloodserum or the spent dialysate.

15. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the potassium sensing devicecomprises a flame photometry detection system that comprises anebulizer, a gas flame source, and a spectral emission detector.

16. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the potassium sensing devicecomprises a fluorescent photo-induced electron transfer sensor.

17. The dialysis system of claim 1, wherein the potassium sensing devicecomprises a laser-induced breakdown spectroscopy detection system.

18. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the potassium sensing devicecomprises a microfluidic optical sensor that comprises a chip, a flowchannel formed in or on the chip, a light source, an optical fiber fordirecting the light source at the channel, a fluorescence detector, anda second optical fiber for directing fluorescence from the channel tothe detector.

19. The dialysis system of claim 1, wherein the potassium sensing devicecomprises:

-   -   an electrocardiogram lead connected to the patient and        configured to sense an electrocardiogram signal corresponding to        a heartbeat of the patient; and    -   a processor configured to analyze the electrocardiogram signal,        determine the amplitude of a T wave component of the        electrocardiogram signal, determine a negative slope of the T        wave component, compute a ratio of the negative slope to the        amplitude, and correlate the ratio to a predetermined blood        serum potassium concentration value stored in a memory.

20. A dialysis system comprising:

-   -   a dialysis machine configured to perform a dialysis treatment on        a patient;    -   a display;    -   a potassium sensing device configured to sense the concentration        of potassium in at least one of (a) the patient's blood, and (b)        spent dialysate resulting from treating the patient with the        dialysis machine, the potassium sensing device further being        configured to generate a measured value of blood potassium        concentration; and    -   a control and computing unit comprising a processor and a        memory, the processor being configured to receive the measured        value of blood potassium concentration, compare the value with        one or more values stored in the memory, and to generate a        display signal based on the comparison, wherein    -   the control and computing unit is in data transfer communication        with the display, the display is configured to receive the        display signal, and the display is configured to display a blood        potassium concentration value or an indication as to whether the        measured value of blood potassium concentration is too high, too        low, or within an acceptable range.

21. The dialysis system of any preceding or followingembodiment/feature/aspect, wherein the potassium sensing devicecomprises an ion selective electrode pair and is configured to calculatethe concentration of potassium in the patient's blood based on ionselective electrode measurements.

The present invention can include any combination of these variousfeatures or embodiments above and/or below as set forth in sentencesand/or paragraphs. Any combination of disclosed features herein isconsidered part of the present invention and no limitation is intendedwith respect to combinable features.

Applicants specifically incorporate the entire contents of all citedreferences in this disclosure. Further, when an amount, concentration,or other value or parameter is given as either a range, preferred range,or a list of upper preferable values and lower preferable values, thisis to be understood as specifically disclosing all ranges formed fromany pair of any upper range limit or preferred value and any lower rangelimit or preferred value, regardless of whether ranges are separatelydisclosed. Where a range of numerical values is recited herein, unlessotherwise stated, the range is intended to include the endpointsthereof, and all integers and fractions within the range. It is notintended that the scope of the invention be limited to the specificvalues recited when defining a range.

Other embodiments of the present invention will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present invention disclosed herein. It is intended thatthe present specification and examples be considered as exemplary onlywith a true scope and spirit of the invention being indicated by thefollowing claims and equivalents thereof.

What is claimed is:
 1. A dialysis system comprising: a dialysis machineconfigured to perform a dialysis treatment on a patient; a potassiumsensing device configured to sense the concentration of potassium in atleast one of (a) the patient's blood serum, and (b) spent dialysateresulting from treating the patient with the dialysis machine, thepotassium sensing device further being configured to generate a sensedvalue of the concentration of blood serum potassium; a control andcomputing unit comprising a processor and a memory, the processor beingconfigured to receive the value, compare the value with one or morevalues stored in the memory, and to generate a control signal based onthe comparison; and a potassium infusion circuit configured to infusepotassium solution into treatment dialysate, replacement fluid, or both,that is to be used by the dialysis machine, wherein the control andcomputing unit is in data transfer communication with the potassiuminfusion circuit, and the potassium infusion circuit is configured toreceive the control signal and infuse potassium solution into thetreatment dialysate, replacement fluid, or both, based on the controlsignal.
 2. The dialysis system of claim 1, wherein the control andcomputing unit is further configured to store the sensed value ofpotassium in the memory.
 3. The dialysis system of claim 1, wherein thememory has stored therein patient-historical data pertaining to sensedblood serum potassium concentration values of the patient obtained underdifferent patient parameters.
 4. The dialysis system of claim 3, whereinthe different patient parameters include at least one parameter based onthe length of time since a last dialysis treatment was carried out onthe patient.
 5. The dialysis system of claim 3, wherein the control andcomputing unit further comprises an input device configured forinputting patient information including a time-since-last-treatmentvalue, and the control and computing unit is configured to generate acontrol signal based on the input patient parameters and thepatient-historical data stored in the memory.
 6. The dialysis system ofclaim 1, wherein the memory has stored therein population datapertaining to sensed blood serum potassium concentration values of apopulation of different patients obtained under different patientparameters.
 7. The dialysis system of claim 6, wherein the control andcomputing unit further comprises an input device configured forinputting patient information including a time-since-last-treatmentvalue, and the control and computing unit is configured to generate acontrol signal based on the input patient parameters and the populationdata stored in the memory.
 8. The dialysis system of claim 1, whereinthe potassium infusion circuit is configured to supply a concentratedsolution of a potassium salt at a first rate and for a first period oftime.
 9. The dialysis system of claim 8, wherein the dialysis machinecomprises a dialysate circuit, the dialysate circuit is configured touse a volume of dialysate, a time value for the first period of time isstored in the memory in a look-up table, and the time value iscategorized in the look-up table based on the volume of dialysate. 10.The dialysis system of claim 9, further comprising an amount ofdialysate equal to the volume of dialysate, in the dialysate circuit.11. The dialysis system of claim 1, wherein the dialysis machinecomprises a dialysate circuit including a sorbent cartridge and thetreatment dialysate comprises regenerated dialysate.
 12. The dialysissystem of claim 1, wherein the potassium sensing device comprises an ionselective electrode pair and is configured to calculate theconcentration of potassium in the patient's blood serum based on ionselective electrode measurements.
 13. The dialysis system of claim 1,wherein the potassium sensing device comprises an ultraviolet absorbancedetection system that comprises an ultraviolet light source and adetector configured to detect ultraviolet light transmitted through thepatient's blood serum or the spent dialysate.
 14. The dialysis system ofclaim 1, wherein the potassium sensing device comprises a near-infraredspectroscopy detection system that comprises a near-infrared source ofradiation, an optical spectral sorting element, and a detectorconfigured to receive spectrally sorted wavelengths from the source ofradiation and that have passed through the patient's blood serum or thespent dialysate.
 15. The dialysis system of claim 1, wherein thepotassium sensing device comprises a flame photometry detection systemthat comprises a nebulizer, a gas flame source, and a spectral emissiondetector.
 16. The dialysis system of claim 1, wherein the potassiumsensing device comprises a fluorescent photo-induced electron transfersensor.
 17. The dialysis system of claim 1, wherein the potassiumsensing device comprises a laser-induced breakdown spectroscopydetection system.
 18. The dialysis system of claim 1, wherein thepotassium sensing device comprises a microfluidic optical sensor thatcomprises a chip, a flow channel formed in or on the chip, a lightsource, an optical fiber for directing the light source at the channel,a fluorescence detector, and a second optical fiber for directingfluorescence from the channel to the detector.
 19. The dialysis systemof claim 1, wherein the potassium sensing device comprises: anelectrocardiogram lead connected to the patient and configured to sensean electrocardiogram signal corresponding to a heartbeat of the patient;and a processor configured to analyze the electrocardiogram signal,determine the amplitude of a T wave component of the electrocardiogramsignal, determine a negative slope of the T wave component, compute aratio of the negative slope to the amplitude, and correlate the ratio toa predetermined blood serum potassium concentration value stored in amemory.
 20. A dialysis system comprising: a dialysis machine configuredto perform a dialysis treatment on a patient; a display; a potassiumsensing device configured to sense the concentration of potassium in atleast one of (a) the patient's blood, and (b) spent dialysate resultingfrom treating the patient with the dialysis machine, the potassiumsensing device further being configured to generate a measured value ofblood potassium concentration; and a control and computing unitcomprising a processor and a memory, the processor being configured toreceive the measured value of blood potassium concentration, compare thevalue with one or more values stored in the memory, and to generate adisplay signal based on the comparison, wherein the control andcomputing unit is in data transfer communication with the display, thedisplay is configured to receive the display signal, and the display isconfigured to display a blood potassium concentration value or anindication as to whether the measured value of blood potassiumconcentration is too high, too low, or within an acceptable range. 21.The dialysis system of claim 20, wherein the potassium sensing devicecomprises an ion selective electrode pair and is configured to calculatethe concentration of potassium in the patient's blood based on ionselective electrode measurements.